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Cantú syndrome is caused by mutations in ABCC9
Abstract
Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.
... Loss-of-function (LOF) and gain-of-function (GOF) mutations in Kir6.2 or SUR1 cause congenital hyperinsulinism (Huopio et al., 2002) and neonatal diabetes (Koster et al., 2000;Gloyn et al., 2004;Babenko et al., 2006), respectively. LOF consequences of Kir6.1 and SUR2 remain incompletely described, but GOF mutations in either subunit cause Cant u syndrome (CS), a complex condition including excess hair growth, coarse facial appearance, cardiomegaly, and lymphedema (Harakalova et al., 2012;van Bon et al., 2012;Brownstein et al., 2013;Cooper et al., 2014Cooper et al., , 2017McClenaghan et al., 2018;Singh et al., 2022). CS incidence is unknown, but there are now >100 individuals with heterozygous pathogenic variants in the International CS Registry , and increased awareness of the clinical phenotype is leading to improved recognition, with probably thousands of affected individuals world-wide. ...
... All CS patients to date are heterozygous for mutations in ABCC9 (SUR2) (Harakalova et al., 2012;van Bon et al., 2012;Grange et al., 2019) or KCNJ8 (Kir6.1) (Brownstein et al., 2013;Cooper et al., 2014;Chihara et al., 2020;Apuril Velgara et al., 2022), and knock-in mouse models show that key CS features result from Kir6.1/SUR2B channel GOF (Huang et al., 2018;McClenaghan et al., 2020a;York et al., 2020). ...
... [R1154Q], [R1154W](van Bon et al., 2012;McClenaghan et al., 2018), and indel1055(Gao et al., 2023) CS mutations. After puromycin treatment, all generated cell lines lost blue fluorescence and showed mCherry red fluorescence in almost every single cell (Fig. 1 ...
Gain-of-function (GOF) of KATP channels, resulting from mutations in either KCNJ8 (encoding Kir6.1) or ABCC9 (encoding SUR2), cause Cantú syndrome (CS), a channelopathy characterized by excess hair growth, coarse facial appearance, cardiomegaly, and lymphedema. Here, we established a pipeline for rapid analysis of CS mutation consequences in Landing pad HEK 293 cell lines stably expressing wild type and mutant human Kir6.1 and SUR2B. Thallium-influx and cell membrane potential, reported by fluorescent Tl-sensitive Fluozin-2 and voltage-sensitive DiBAC4(3) dyes, respectively, were used to assess channel activity. In the Tl-influx assay, CS-associated Kir6.1 mutations increased sensitivity to the KATP channel activator, pinacidil, but there was strikingly little effect of pinacidil for any SUR2B mutations, reflecting unexpected differences in the molecular mechanisms of Kir6.1 versus SUR2B mutations. Compared to the Tl-influx assay, the DiBAC4(3) assay presents more significant signal changes in response to subtle KATP channel activity changes, and all CS mutants (both Kir6.1 and SUR2B), but not WT channels, caused marked hyperpolarization, demonstrating that all mutants were activated under ambient conditions in intact cells. Most SUR2 CS mutations were markedly inhibited by <100nM glibenclamide, but sensitivity to inhibition by glibenclamide, repaglinide, and PNU37883A, was markedly reduced for Kir6.1 CS mutations. Understanding functional consequences of mutations can help with disease diagnosis and treatment. The analysis pipeline we have developed has the potential to rapidly identify mutational consequences, aiding future CS diagnosis, drug discovery, and individualization of treatment. Significance Statement We have developed new fluorescence-based assays of channel activities and drug sensitivities of Cantú syndrome (CS) mutations in human Kir6.1/SUR2B-dependent KATP channels, showing that Kir6.1 mutations increase sensitivity to activation by potassium channel openers, while SUR2B mutations markedly reduce KCO sensitivity. However, both Kir6.1 and SUR2B CS mutations are both more hyperpolarized than WT cells under basal conditions, confirming pathophysiologically relevant gain-of-function, validating DiBAC4(3) fluorescence to characterize hyperpolarization induced by KATP channel activity under basal, non KCO-activated conditions.
... Additional clinical features comprise wrinkled and/or loose skin, hyperextensible joints, and developmental delay (Grange et al., 2006Nichols et al., 2013;Scurr et al., 2011). Heterozygous gain-of-function mutations in ABCC9 and, rarely, in KCNJ8, encoding the regulatory (SUR2) and pore-forming (Kir6.1) subunits, respectively, of ATP-sensitive potassium (K ATP ) channels cause CS (Brownstein et al., 2013;Cooper et al., 2014;Harakalova et al., 2012;van Bon et al., 2012). By patch-clamp electrophysiology, functional characterization of ABCC9 and KCNJ8 mutations revealed increased channel activity via different molecular mechanisms, such as increase in intrinsic open probability and augmented magnesium-nucleotide-mediated activation (Cooper et al., , 2015McClenaghan et al., 2018). ...
... Identification of the two KCNQ1 missense variants leading to an increase in potassium conductance via hyperpolarization and associated with growth hormone deficiency and maternally inherited gingival overgrowth further confirms a role of potassium channels in the development of gingival hyperplasia (Tommiska et al., 2017). Interestingly, CS is also associated with increased K þ channel activity due to amino acid changes in the Kir6.1 or SUR2 subunits (Cooper et al., , 2015McClenaghan et al., 2018), and gingival overgrowth and shortening of distal phalanges of fingers have occasionally been reported in individuals with ABCC9 mutation (Afifi et al., 2016;Czeschik et al., 2013;van Bon et al., 2012). ...
... Here we report four novel ABCC9 variants, p.(Pro252Leu), p. (Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His), and two known amino acid changes, p.(Thr1202Met) and p.(Arg1154Gln) (Czeschik et al., 2013;Grange et al., 2019;Harakalova et al., 2012;Hiraki et al., 2014;van Bon et al., 2012), in nine individuals with clinical features fitting or suggestive of CS. All patients shared coarse face, epicanthal folds, full lips, and hypertrichosis ( Figs. 1-3, Table 1). ...
Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding heterooctameric ATP-sensitive potassium (KATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K⁺ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.
... Published on February 1, 2024 as DOI: 10.1124/molpharm.123.000783 at ASPET Journals on February 2, 2024 molpharm.aspetjournals.org Downloaded from mutations in KCNJ8 or ABCC9 result in Cantu syndrome, a rare genetic disorder characterized by excessive hair growth, distinctive facial features, and an enlarged heart (Brownstein et al., 2013;Cooper et al., 2014;Harakalova et al., 2012;Li et al., 2013;Nichols et al., 2013;van Bon et al., 2012). More than 50% of Cantu patients are born with symptomatic PDA (McClenaghan and Nichols, 2022). ...
... Gain-of-function mutations in Kir6.1 or SUR2B result in Cantu syndrome, an autosomal dominant disorder that affects multiple organ systems, including the cardiovascular system (Brownstein et al., 2013;Cooper et al., 2014;Harakalova et al., 2012;Li et al., 2013;van Bon et al., 2012) More than half of Cantu patients are born with symptomatic patent ductus arteriosus (PDA) (Nichols, 2023). We and others have shown that Kir6.1/SUR2B expression is enriched in DA vessels and may represent a druggable target for treating PDA Shelton et al., 2018;Yarboro et al., 2018). ...
Vascular smooth muscle KATP channels critically regulate blood flow and blood pressure by modulating vascular tone and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular KATP) over Kir6.2/SUR1 (pancreatic KATP) has eluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N-aryl-N'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC50 of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus vessels, VU0542270 induced ductus arteriosus constriction in a dose-dependent manner similar to that of the nonspecific KATP channel inhibitor glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific KATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. SIGNIFICANCE STATEMENT: Small-molecule inhibitors of vascular smooth muscle KATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis; however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, this study describes the discovery and characterization of the first vascular-specific KATP channel inhibitor, VU0542270.
... ABCC9 and KCNJ8 encode subunits of cardiac ATP-sensitive potassium (K ATP ) channels, SUR2 and Kir6.1, respectively [36,37]. These genes have been implicated in DCM, Cantú syndrome, atrial fibrillation, Brugada (J-wave) syndrome, and sudden death in infants and adults [7,8,[38][39][40][41][42][43][44][45][46][47]. Exonic sequencing of ABCC9 and KCNJ8 in an affected dog revealed two ABCC9 variants that were absent from controls (Table 1). ...
... Another nearby variant, p.M1198I (rs199900459), was reported in a patient with left ventricular non-compaction cardiomyopathy [56]. The TMD2 is also a common site for gain of function variants causal for Cantú syndrome [42,43]. The pathogenicity of p.R1186Q is supported by the high conservation of the R1186 residue and its location in a hot spot for cardiac phenotypes. ...
Sudden cardiac death in the young (SCDY) is a devastating event that often has an underlying genetic basis. Manchester Terrier dogs offer a naturally occurring model of SCDY, with sudden death of puppies as the manifestation of an inherited dilated cardiomyopathy (DCM). We performed a genome-wide association study for SCDY/DCM in Manchester Terrier dogs and identified a susceptibility locus harboring the cardiac ATP-sensitive potassium channel gene ABCC9. Sanger sequencing revealed an ABCC9 p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (n = 26). None of the controls genotyped (n = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (p = 4 × 10−42 for the association of homozygosity for ABCC9 p.R1186Q with SCDY/DCM). This variant exists at low frequency in human populations (rs776973456) with clinical significance previously deemed uncertain. The results of this study further the evidence that ABCC9 is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.
... In mammals, Kir6.2 is coupled with SUR1 in the pancreas and in neurons, Kir6.2 is coupled with SUR2A in striated muscles and Kir6.1 is coupled with SUR2B in VSM. The discovery of gain-of-function (GOF) or loss-of-function (LOF) mutations in KCNJ8 and ABCC9 as causes of Cantú Syndrome (CS) (van Bon et al. 2012;Harakalova et al. 2012a;Brownstein et al. 2013;Cooper et al. 2014Cooper et al. , 2017McClenaghan et al. 2018) or ABCC9-related Intellectual Disability and Myopathy syndrome (AIMS) (Smeland et al. 2019), respectively, provides a clear illustration of the pathologic potential of K ATP channels. ...
... Recent studies have shown that GOF and LOF in KCNJ8 (Kir6.1) and ABCC9 (SUR2) underlie human Cantú syndrome and ABCC9-related Intellectual Disability and Myopathy syndrome (AIMS), respectively (van Bon et al. 2012;Harakalova et al. 2012b;Smeland et al. 2019). In previous studies, we have shown that zebrafish carrying disease-causing mutations in the equivalent kcnj8 and abcc9 loci reiterate essential features of these syndromes (Tessadori et al. 2018;Smeland et al. 2019) and here we have shown that each of these CS mutations causes increased VSM K ATP conductance, but cardiac channel properties are only affected in the SUR2 mutants. ...
ATP‐sensitive potassium channels (KATP channels) are hetero‐octameric nucleotide‐gated ion channels that couple cellular metabolism to excitability in various tissues. In the heart, KATP channels are activated during ischaemia and potentially during adrenergic stimulation. In the vasculature, they are normally active at a low level, reducing vascular tone, but the ubiquitous nature of these channels leads to complex and poorly understood channelopathies as a result of gain‐ or loss‐of‐function mutations. Zebrafish (ZF) models of these channelopathies may provide insights to the link between molecular dysfunction and complex pathophysiology, but this requires understanding the tissue dependence of channel activity and subunit specificity. Thus far, direct analysis of ZF KATP expression and functional properties has only been performed in pancreatic β‐cells. Using a comprehensive combination of genetically modified fish, electrophysiology and gene expression analysis, we demonstrate that ZF cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. However, in contrast to mammalian cardiovascular KATP channels, ZF channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. The results provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9‐related Intellectual Disability and Myopathy syndrome.
Key points
Zebrafish cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts.
In contrast to mammalian cardiovascular KATP channels, zebrafish channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM.
We provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9‐related Intellectual Disability and Myopathy syndrome.
... CS is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia, and multiple cardiovascular abnormalities, including cardiomegaly, hypertrophy, pericardial effusion, pulmonary hypertension, and patent ductus arteriosus and cerebrovascular defects (2)(3)(4)(5). Multiple reports have now confirmed that autosomal dominant gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K ATP ) channels, represent the genetic basis of CS (6)(7)(8)(9)(10)(11). The severity of features varies widely between individuals, although genotype-phenotype correlations have been difficult to establish; interestingly, patients with the same mutation can span the clinical spectrum (6,7,12,13). ...
... Multiple reports have now confirmed that autosomal dominant gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K ATP ) channels, represent the genetic basis of CS (6)(7)(8)(9)(10)(11). The severity of features varies widely between individuals, although genotype-phenotype correlations have been difficult to establish; interestingly, patients with the same mutation can span the clinical spectrum (6,7,12,13). ...
Cantu Syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by ~30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of human SUR2[R1154Q] mutation to the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed an underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing of SUR2 cDNA revealed divergent transcripts, one encoding full length SUR2 protein, and the other with in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in ~40% and ~90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in non-functional channels. SUR2[R1154Q] CS patient tissue and iPSC-derived cardiomyocytes showed only full length SUR2 transcripts, although further studies will be required to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS.
... In smooth muscle, Kir6.1/SUR2B K ATP activity is a key determinant of electrical excitability and consequent contractility in blood and lymphatic vessels, as well as in bladder and uterine muscle [11][12][13][14][15] There have now been multiple reports of mutations in the ABCC9 and KCNJ8 genes (which encode for SUR2 and Kir6.1 respectively) associated with the complex heritable disorder, Cantu Syndrome (CS) [16][17][18][19][20][21]. CS patients exhibit diverse cardiovascular features including: dilated and tortuous vessels, cardiomegaly, electrophysiological alterations in the cardiac conduction system, decreased neuro-vascular coupling and persistence of fetal circulation [16][17][18][20][21][22][23][24][25]] . ...
... K ATP activity is a key determinant of electrical excitability and consequent contractility in blood and lymphatic vessels, as well as in bladder and uterine muscle [11][12][13][14][15] There have now been multiple reports of mutations in the ABCC9 and KCNJ8 genes (which encode for SUR2 and Kir6.1 respectively) associated with the complex heritable disorder, Cantu Syndrome (CS) [16][17][18][19][20][21]. CS patients exhibit diverse cardiovascular features including: dilated and tortuous vessels, cardiomegaly, electrophysiological alterations in the cardiac conduction system, decreased neuro-vascular coupling and persistence of fetal circulation [16][17][18][20][21][22][23][24][25]] . An emerging model for the molecular basis of CS is that missense mutations in ABCC9 or KCNJ8 result in increased K ATP channel activity, and consequent reduced smooth muscle excitability and contractility [26,27]. ...
The complex cardiovascular disorder Cantu Syndrome arises from gain-of-function mutations in either KCNJ8 or ABCC9 , the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K ATP ) channels. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determine the mechanism by which K ATP function is altered by several mutations in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/W in TMD2. Mutations were engineered at their equivalent position in rat SUR2A (D207E, Y981S, G985E, M1056I and R1150Q/W) and functional effects were investigated using macroscopic rubidium ( ⁸⁶ Rb ⁺ ) efflux assays and patch clamp electrophysiology. The results show that D207E increases K ATP activity by increasing intrinsic stability of the open state, whilst the cluster of Y981S/G985E/M1056I mutations, as well as R1150Q/W, augment Mg-nucleotide activation. The response of mutant channels to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS, was also tested. There was no major effect on glibenclamide sensitivity for the D207E, Y981S, G985E or M1056I mutations, but glutamine and tryptophan substitution at R1150 resulted in significant decreases in potency.
... Cantú Syndrome (CS) is a rare congenital disorder associated with a range of cardiovascular (CV) abnormalities, including dilated and tortuous blood vessels, pericardial effusion, and dramatically enlarged hearts, as well as frequent reports of pulmonary hypertension and exercise intolerance (Cooper et al., 2014, Grange et al., 2006, Leon Guerrero et al., 2016, van Bon et al., 2012, Grange et al., 2019, Scurr et al., 2011. CS is caused by gain-of-function (GoF) mutations in ABCC9 or KCNJ8, which encode the SUR2 and Kir6.1 subunits of cardiovascular ATP-sensitive potassium (K ATP ) channels, respectively (Harakalova et al., 2012, van Bon et al., 2012, Cooper et al., 2014, Brownstein et al., 2013. ...
... Cantú Syndrome (CS) is a rare congenital disorder associated with a range of cardiovascular (CV) abnormalities, including dilated and tortuous blood vessels, pericardial effusion, and dramatically enlarged hearts, as well as frequent reports of pulmonary hypertension and exercise intolerance (Cooper et al., 2014, Grange et al., 2006, Leon Guerrero et al., 2016, van Bon et al., 2012, Grange et al., 2019, Scurr et al., 2011. CS is caused by gain-of-function (GoF) mutations in ABCC9 or KCNJ8, which encode the SUR2 and Kir6.1 subunits of cardiovascular ATP-sensitive potassium (K ATP ) channels, respectively (Harakalova et al., 2012, van Bon et al., 2012, Cooper et al., 2014, Brownstein et al., 2013. Kir6.1 and SUR2 are co-expressed in smooth muscle cells, where K ATP channel activation reduces cellular excitability and provokes vasodilation (Nelson, 1993, Nelson and Brayden, 1993, Li et al., 2013, Aziz et al., 2014. ...
Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú Syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of CV remodeling in CS, is unknown. Using genome-edited mouse models of CS, we sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin-angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and is accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.
... Myhre syndrome should not be mistaken for Cantu syndrome (Grange et al., 2006;van Bon et al., 2012) or the Camptodactyly-Arthropathy-Coxa vara-Pericarditis syndrome (Faivre et al., 2000;Taşar et al., 2014). MULIBREY dwarfism is an autosomal recessive syndrome-, caused by mutations in TRIM37, associated with both pericardial constriction and myocardial restrictive disease (Eerola et al., 2007;Lipsanen-Nyman et al., 2003). ...
Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4 . Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number ( n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies.
... Например, транспортер ABCC2 участвует в транспорте конъюгированных лекарственных средств и токсинов в желчь и мочу [25], а мутации в этом гене ассоциированы с синдромом Дубина-Джонсона -заболеванием печени, характеризующимся гипербилирубинемией [9]. Дисфункциональные мутантные продукты гена ABCC8 связаны с гипогликемией и гиперинсулизмом [9], в то время как нарушения в ABCC9 -с кардиомиопатией [26] и другими заболеваниями, связанными с пороками сердца [27,28]. ...
ABC transporters (ATP Binding Cassette (ABC) transporters) are proteins, which play a dual role in the substances transport across the membrane. On the one hand, they transport nutrients and other molecules inside the cell to supply the necessary nutrients, on the other hand, these proteins excrete some endogenous and exogenous substrates from the cell to maintain their homeostasis in the body and prevent from effects of aggressive environment. ABC transporters play a role in the pathogenesis of various metabolic disorders. In addition, a large amount of evidence has been accumulated about the participation of these proteins in oncogenesis because of their involvement into initiation, progression, invasion and metastasis of tumors, as well as development of multidrug resistance phenotype. Currently, these proteins are attractive therapeutic targets, influence on which can significantly increase the effectiveness of anticancer therapy and improve the prognosis of patients with oncological diseases, including recurrent, metastatic and inoperable forms.
The review provides information on drugs that affect the functional activity of ABC transporters and the mechanisms of their action, and also presents the results of clinical trials of these inhibitors.
... The ABCC9 gene encodes the SUR2 protein and gain-of-function mutations were associated with Cantu syndrome, a rare condition characterized by hypertrichosis, a distinctive facial appearance, osteochondroplasia, cardiac defects and pericardial effusion [31]. Rare cases of PH with complex and multiple mechanisms have been reported in Cantu syndrome [32][33][34]. ...
The ATP-sensitive potassium channels (K ATP ) and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants.
This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed.
Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analyzed data from the WHO pharmacovigilance database (Vigibase). Significant disproportionality signals linking diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.
... A syndrome of congenital hypertrichosis, cardiomegaly, and musculoskeletal malformations was initially reported by Cantú and associates [1] . Cantú syndrome is caused by variants in the ABCC9 gene that result in a gain of function in adenosine triphosphate-sensitive potassium (K ATP ) channels [2,3] . ...
A range of pulmonary arterial pressures was observed in three related patients with Cantú syndrome. The incident patient developed a moderately high pulmonary vascular resistance. Several factors influenced the severity of his pulmonary vascular disease and the events, which ultimately resulted in his death. However, he had an acute improvement in blood pressure and respiratory support after a single dose of glyburide when he was critically ill. The father and sister of the incident patient have evidence of mildly increased pulmonary arterial pressure with normal pulmonary vascular resistance. They are being treated with glyburide to potentially decrease the high cardiac output associated with a gain in KATP channel function. Additional experience with glyburide or other KATP channel inhibitors is needed to determine the most appropriate agent, dose, time, and duration of treatment for patients with Cantú syndrome.
... SUR2 proteins are encoded by the ABCC9 gene. The loss-of-function mutations of the ABCC9 gene cause dilated cardiomyopathy 6 , familial atrial fibrillation 7 , and intellectual disability myopathy syndrome 8 , while the gain-of-function mutations of ABCC9 lead to Cantu syndrome in humans 9,10 . Although SUR1, SUR2A, and SUR2B share high sequence homologies, they have differential responses to Mg-ADP activation and show variable sensitivities to drugs such as K ATP openers [11][12][13][14][15] . ...
KATP channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing KATP channels differ from other subtypes in their sensitivity to Mg-ADP activation. However, the underlying structural mechanism remains poorly understood. Here we present a series of cryo-EM structures of SUR2A in the presence of different combinations of Mg-nucleotides and the allosteric inhibitor repaglinide. These structures uncover regulatory helix (R helix) on the NBD1-TMD2 linker, which wedges between NBD1 and NBD2. R helix stabilizes SUR2A in the NBD-separated conformation to inhibit channel activation. The competitive binding of Mg-ADP with Mg-ATP to NBD2 mobilizes the R helix to relieve such inhibition, allowing channel activation. The structures of SUR2B in similar conditions suggest that the C-terminal 42 residues of SUR2B enhance the structural dynamics of NBD2 and facilitate the dissociation of the R helix and the binding of Mg-ADP to NBD2, promoting NBD dimerization and subsequent channel activation.
... We describe the natural history of a cardiac phenotype characterized by LVH with enhanced ventricular function and high-output state caused by genetically determined vasodilatation, in a cohort of subjects with Cantu syndrome (CS; Online Mendelian Inheritance in Man number 239850), an autosomal dominant condition caused by gain-of-function variants in ABCC9 and, less commonly, in KCNJ8, which encode the regulatory (Sulfonylurea receptor 2 [SUR2]) and pore-forming (inwardly rectifying potassium channel family member 6.1) subunits, respectively, of K ATP (ATP-sensitive potassium) channels. [3][4][5][6] Subjects with CS exhibit a wide constellation of clinical features, [7][8][9] with congenital hypertrichosis, osteochondrodysplasia, and characteristic facies. We describe the longitudinal cardiovascular phenotype in 31 subjects with CS and discuss the potential mechanistic basis, natural history of the high-output state, and the clinical implications of this sentinel example of highoutput cardiac hypertrophy associated with primary decreased systemic vascular resistance. ...
Background
Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high‐output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities.
Methods and Results
We sought to systematically characterize high‐output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain‐of‐function variants in ABCC9 , which encodes cardiovascular K ATP (ATP‐sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3–32 years], body mass index 19.9 [16.5–22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7–103.0] g/m ² in CS, n=30; 26.6 [24.1–32.8] g/m ² in controls, n=17; P <0.0001) and low blood pressure (systolic 94.5 [90–103] mm Hg in CS, n=17; 109 [98–115] mm Hg in controls, n=17; P =0.0301; diastolic 60 [56–66] mm Hg in CS, n=17; 69 [65–72] mm Hg in control, n=17; P =0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long‐term follow‐up.
Conclusions
The data define the natural history of high‐output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long‐term consequences of high‐output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high‐output heart failure.
... First described as a distinct syndrome in 1982 (50), Cantú syndrome (CS; MIM 239850) is a multiorgan disorder characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia, multiple cardiovascular features (51), and potentially lethal pulmonary hypertension and bronchopulmonary dysplasia (52). Genetically associated with ABCC9 in 2012 (53,54) and with KCNJ8 in 2014 (55,56), over 30 mutations have since been identified in more than 100 patients (51,52,(57)(58)(59)(60)(61)(62). All assessed mutations lead to recombinant K ATP channel GOF (56,63,64). ...
Ubiquitously expressed throughout the body, ATP-sensitive potassium (K ATP ) channels couple cellular metabolism to electrical activity in multiple tissues; their unique assembly as four Kir6 pore-forming subunits and four sulfonylurea receptor (SUR) subunits has resulted in a large armory of selective channel opener and inhibitor drugs. The spectrum of monogenic pathologies that result from gain- or loss-of-function mutations in these channels, and the potential for therapeutic correction of these pathologies, is now clear. However, while available drugs can be effective treatments for specific pathologies, cross-reactivity with the other Kir6 or SUR subfamily members can result in drug-induced versions of each pathology and may limit therapeutic usefulness. This review discusses the background to K ATP channel physiology, pathology, and pharmacology and consider the potential for more specific or effective therapeutic agents.
Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Two decades after their cloning, the first definitive demonstration of the pathological consequences of mutations in KCNJ8 and ABCC9 in humans was provided by the identification of multiple missense mutations in both genes which converge in the same clinical presentation, Cantú Syndrome (CS) [28][29][30][31][32][33] . CS is a rare, heritable disorder characterized by hypertrichosis, distinct facial features, and a range of striking cardiovascular abnormalities, including decreased systemic vascular resistance and drastic cardiomegaly 34; 35 . ...
Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K ATP ) channels expressed in a wide range of tissues. Extensive study has implicated roles for these channel subunits in diverse physiological functions. Together they generate the predominant K ATP conductance in vascular smooth muscle and are the target of vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction in disease have been suggested based on studies of animal models and human genetic discoveries. In recent years, it has become clear that gain-of-function (GoF) mutations in both genes result in Cantu Syndrome (CS) - a complex, multi-system disorder. There is currently no targeted therapy for CS, but studies of mouse models of the disease reveal that pharmacological reversibility of cardiovascular and gastrointestinal pathologies can be achieved by administration of the K ATP channel inhibitor, glibenclamide. Here we review the function, structure, and physiological and pathological roles of Kir6.1/SUR2B channels, with a focus on CS. Recent studies have led to much improved understanding of the underlying pathologies and the potential for treatment, but important questions remain: Can the study of genetically defined CS reveal new insights to Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common disease? And is our pharmacological armoury adequately stocked.
... Because of its unique properties, K ATP channels play essential roles in many key physiological processes, such as hormone secretion 2 , cardiac preconditioning 3 , and vasodilation 4 . The genetic mutations of genes encoding K ATP channels lead to a spectrum of diseases, ranging from metabolic syndrome to cardiovascular diseases and CNS disorders, including neonatal diabetes or even the Developmental delay, Epilepsy, and Neonatal Diabetes" (DEND) syndrome 5 , hyperinsulinaemic hypoglycemia of infancy 5 , dilated cardiomyopathy 6 , familial atrial fibrillation 7 , Cantú syndrome 8,9 and intellectual disability myopathy syndrome 10 . K ATP channels are also important drug targets. ...
ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type KATP openers.
... These channels participate in many physiological processes and are implicated in several pathological conditions. Genetic mutations of K ATP channels in humans lead to a range of diseases, including neonatal diabetes mellitus 3 , hyperinsulinaemic hypoglycemia of infancy 3 , dilated cardiomyopathy 4 , Cantu syndrome 5,6 , familial atrial fibrillation 7 and intellectual disability myopathy syndrome 8 . K ATP are validated drug targets and are modulated by both pharmaceutical inhibitors and activators, many of which have been approved for use in the clinic. ...
ATP-sensitive potassium channels (KATP), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing KATP channels by class of small molecule drugs known as KATP openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, KATP openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to KATP and how they activate the channel remains elusive. Here, we present cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct KATP openers that are specific to SUR2. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TM10, TM11, TM12, TM14, and TM17. These KATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.
... Cantù syndrome (CS, MIM # 239850) is a rare AD disorder caused by heterozygous gain-of-function variants in ABCC9 (97%, OMIM # 601439) and, rarely, in KCNJ8 (1-2%, OMIM # 600935), encoding the regulatory (SUR2) and pore-forming (Kir6.1) subunits, respectively, of ATP-sensitive potassium (KATP) channels [162]. ...
Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives’ recurrence risk calculation. The previous points represent a cornerstone in patients’ empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective “autophagy” process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
... In vascular smooth muscle, K ATP activation leads to membrane hyperpolarization and vasodilation (5), while inhibition or deletion causes membrane depolarization, vasoconstriction, and hypertension (5)(6)(7)(8). Mutations in the vascular K ATP channel genes (KCNJ8 and ABCC9) cause Cant u syndrome (9)(10)(11), a severe pleiotropic systemic hypotension disorder including hypertrichosis, osteochondrodysplasia, and cardiomegaly (12). K ATP channel gating by intracellular ATP and ADP involves allosteric sites on both subunits. ...
Significance
Vascular K ATP channels formed by the potassium channel Kir6.1 and its regulatory protein SUR2B maintain blood pressure in the physiological range. Overactivity of the channel due to genetic mutations in either Kir6.1 or SUR2B causes severe cardiovascular pathologies known as Cantú syndrome. The cryogenic electron microscopy structures of the vascular K ATP channel reported here show multiple, dynamically related conformations of the regulatory subunit SUR2B. Molecular dynamics simulations reveal the negatively charged ED-domain in SUR2B, a stretch of 15 glutamate (E) and aspartate (D) residues not previously resolved, play a key MgADP-dependent role in mediating interactions at the interface between the SUR2B and Kir6.1 subunits. Our findings provide a mechanistic understanding of how channel activity is regulated by intracellular MgADP.
... In vascular smooth muscle, K ATP activation leads to membrane hyperpolarization and vasodilation 5 , while inhibition or deletion causes membrane depolarization, vasoconstriction and hypertension [5][6][7][8] . Mutations in the vascular K ATP channel genes (KCNJ8 and ABCC9) cause Cantú syndrome [9][10][11] , a severe pleiotropic systemic hypotension disorder including hypertrichosis, osteochondrodysplasia, and cardiomegaly 12 . K ATP channel gating by intracellular ATP and ADP involves allosteric sites on both subunits. ...
Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantu syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined the first cryoEM structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational propeller and quatrefoil geometries surrounding their Kir6.1 core. The previously unseen ED-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. MD simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated and MgADP-bound activated conformations wherein the ED-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.
... We already noticed clinical overlap of ZLS and CS and found early DD, hypertrichosis, gingival enlargement, joint laxity, and hypoplasia of terminal phalanges and nails in one or several of the nine recently reported individuals with a dominant variant in ABCC9 [26]. Dominant variants in ABCC9 and, rarely, in KCNJ8, encoding the regulatory (SUR2) and pore-forming (Kir6.1) subunits, respectively, of ATP-sensitive potassium (K ATP ) channels cause CS [27][28][29][30]. Distinctive craniofacial features of CS, including coarse facial features, low anterior hairline, wide nasal bridge, epicanthal folds, full lips, and hypertrichosis of the forehead [31], can also be seen in individuals with dominant KCNN3 or KCNK4 variant (Figs. 1 and 2). ...
Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
... Cantú syndrome (CS; OMIM 239850) is caused by heterozygous activating missense mutations in ABCC9 (Harakalova et al., 2012;van Bon et al., 2012) or KCNJ8 (Brownstein et al., 2013;Cooper et al., 2014), which respectively encode the regulatory sulfonylurea subunit SUR2 and inwardrectifying subunit K ir 6.1 of K ATP . Clinical features of CS may include macrosomia and generalized oedema at birth, with marked hypertrichosis affecting the forehead and body. ...
Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.
... Several of the Rbm24-regulated spliced genes have been reported to play crucial roles in cardiac and skeletal muscle development (i.e. Naca, Fxr1, Abcc9, Slc25a3, Usp25 and Usp28) [15][16][17][18][19][20] . More recently, Liu et al. generated a conditional knockout model for Rbm24, to be able to circumvent the embryonic lethality and study its role in the postnatal heart 21 . ...
RNA-binding proteins are key regulators of post-transcriptional processes such as alternative splicing and mRNA stabilization. Rbm24 acts as a regulator of alternative splicing in heart and skeletal muscle, and is essential for sarcomere assembly. Homozygous inactivation of Rbm24 in mice disrupts cardiac development and results in embryonic lethality around E12.5. In the present study, we generated somatic Rbm24 knockout (KO) mice and investigated the effects of reduced levels of Rbm24 in the adult heart. Due to the embryonic lethality of Rbm24 KO mice, we examined cardiac structure and function in adult Rbm24 heterozygotes (HETs). Rbm24 protein expression was 40% downregulated in HET hearts compared to WT hearts. Force measurements on isolated membrane-permeabilized myocytes showed increased sarcomere slack length and lower myofilament passive stiffness in adult Rbm24 HET compared to wildtype cardiomyocytes. As a result of the differences in sarcomere slack length, the relations between force development and sarcomere length differed between WT and Rbm24 HET hearts. No differences in sarcomere structure and titin isoform composition were observed. Likewise, in vivo cardiac function and myocardial structure was unaltered in Rbm24 HET mice compared to WT, at baseline and upon pressure overload after transverse aortic constriction. In conclusion, we generated a somatic Rbm24 KO model and recapitulated the previously reported embryonic phenotype. In adult Rbm24 HET cardiomyocytes we observed increased sarcomere slack length, but no difference in sarcomere structure and cardiac function.
... Recent studies have shown that Cantú syndrome (CS), a complex multi-organ disorder, is caused by gain-of-function (GoF) mutations in KCNJ8 (Kir6.1) or ABCC9 (SUR2) (Harakalova et al. 2012;van Bon et al. 2012;Brownstein et al. 2013;Cooper et al. 2014). CS patients are characterized by a constellation of symptoms which typically includes congenital hypertrichosis and dysmorphic facial features (Cantú et al. 1982;Grange et al. 2019): 80% of CS patients exhibit cardiovascular abnormalities, including hypotension, cardiomegaly, patent ductus arteriosus and pulmonary hypertension (Grange et al. 1993;Nichols et al. 2013;Levin et al. 2016); 50% of CS patients have symptomatic patent ductus arteriosus, compared to 0.05-0.2% in the general population, which requires surgical ligation or, if untreated, eventually leads to pulmonary hypertension Cooper et al. 2014). ...
Key points
Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques.
Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil.
Smooth muscle‐specific expression of Kir6.1 gain‐of‐function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the KATP inhibitor glibenclamide. In contrast, lymphatic endothelial‐specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function.
The high sensitivity of LSM to KATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain‐of‐function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent.
Abstract
This study aimed to understand the functional expression of KATP channel subunits in distinct lymphatic cell types, and assess the consequences of altered KATP channel activity on lymphatic pump function. KATP channel subunits Kir6.1 and SUR2B were expressed in mouse lymphatic muscle by PCR, but only Kir6.1 was expressed in lymphatic endothelium. Spontaneous contractions of popliteal lymphatics from wild‐type (WT) (C57BL/6J) mice, assessed by pressure myography, were very sensitive to inhibition by the SUR2‐specific KATP channel activator pinacidil, which hyperpolarized both mouse and human lymphatic smooth muscle (LSM). In vessels from mice with deletion of Kir6.1 (Kir6.1−/−) or SUR2 (SUR2[STOP]) subunits, contractile parameters were not significantly different from those of WT vessels, suggesting that basal KATP channel activity in LSM is not an essential component of the lymphatic pacemaker, and does not exert a strong influence over contractile strength. However, these vessels were >100‐fold less sensitive than WT vessels to pinacidil. Smooth muscle‐specific expression of a Kir6.1 gain‐of‐function (GoF) subunit resulted in severely impaired lymphatic contractions and hyperpolarized LSM. Membrane potential and contractile activity was partially restored by the KATP channel inhibitor glibenclamide. In contrast, lymphatic endothelium‐specific expression of Kir6.1 GoF subunits had negligible effects on lymphatic contraction frequency or amplitude. Our results demonstrate a high sensitivity of lymphatic contractility to KATP channel activators through activation of Kir6.1/SUR2‐dependent channels in LSM. In addition, they offer an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain‐of‐function mutations in genes encoding Kir6.1/SUR2.
... Mutations in the ABCC9 gene are known to cause Cantu syndrome, a disease characterized by a number of developmental abnormalities and congenital heart disease. 126 ABCC9 mutations also have been identified in patients with DCM and paroxysmal atrial fibrillation. 127,128 The causal role of ABCC9 mutations in these phenotypes remain to be established. ...
Cardiac arrhythmias are common, often the first, and sometimes the life-threatening manifestations of hereditary cardiomyopathies. Pathogenic variants in several genes known to cause hereditary cardiac arrhythmias have also been identified in the sporadic cases and small families with cardiomyopathies. These findings suggest a shared genetic etiology of a subset of hereditary cardiomyopathies and cardiac arrhythmias. The concept of a shared genetic etiology is in accord with the complex and exquisite interplays that exist between the ion currents and cardiac mechanical function. However, neither the causal role of cardiac arrhythmias genes in cardiomyopathies is well established nor the causal role of cardiomyopathy genes in arrhythmias. To the contrary, secondary changes in ion currents, such as post-translational modifications, are common and contributors to the pathogenesis of arrhythmias in cardiomyopathies through altering biophysical and functional properties of the ion channels. Moreover, structural changes, such as cardiac hypertrophy, dilatation, and fibrosis provide a pro-arrhythmic substrate in hereditary cardiomyopathies. Genetic basis and molecular biology of cardiac arrhythmias in hereditary cardiomyopathies are discussed.
This chapter reviews acquired hair disorders, including common scarring and non‐scarring alopecia presentations, conditions characterised by excessive body hair growth and acquired hair shaft disorders. We also describe the biology of normal hair follicles, including structure, hair cycle control and immunity, to better understand the mechanisms underlying these conditions. We present methods for clinical assessment, recommended investigation and management of each disease, and present summaries of frequently used therapeutics and cosmetic options employed when treating these problems.
Congenital and inherited disorders of hair growth and differentiation, also known as genotrichoses, can be subdivided into conditions associated with either excessive hair growth, known as hypertrichoses , or defective hair development or alopecias . Some of these disorders feature isolated hair abnormalities, others are associated with extracutaneous manifestations and as such require careful surveillance or timely interventions for possible complications.
SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides.
Inherited hair disorders form a highly phenotypically and genetically heterogeneous group, which result from abnormal regulation of hair growth and differentiation leading either to excessive or defective hair follicle development. Accurate diagnosis is essential as many of these disorders are indicative of sometimes occult and/or delayed systemic manifestations.
The genetic basis of the human vocal system is largely unknown, as are the sequence variants that give rise to individual differences in voice and speech. Here, we couple data on diversity in the sequence of the genome with voice and vowel acoustics in speech recordings from 12,901 Icelanders. We show how voice pitch and vowel acoustics vary across the life span and correlate with anthropometric, physiological, and cognitive traits. We found that voice pitch and vowel acoustics have a heritable component and discovered correlated common variants in ABCC9 that associate with voice pitch. The ABCC9 variants also associate with adrenal gene expression and cardiovascular traits. By showing that voice and vowel acoustics are influenced by genetics, we have taken important steps toward understanding the genetics and evolution of the human vocal system.
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, imposing an increasing global health burden. Cardiac ion channels (voltage-gated NaV, CaV, KVs, and others) synergistically shape the cardiac action potential (AP) and control the heartbeat. Dysfunction of these channels, due to genetic mutations, transcriptional or post-translational modifications, may disturb the AP and lead to arrhythmia, a major risk for CVD patients. Although there are five classes of anti-arrhythmic drugs available, they can have varying levels of efficacies and side effects on patients, possibly due to the complex pathogenesis of arrhythmias. As an alternative treatment option, Chinese herbal remedies have shown promise in regulating cardiac ion channels and providing anti-arrhythmic effects. In this review, we first discuss the role of cardiac ion channels in maintaining normal heart function and the pathogenesis of CVD, then summarize the classification of Chinese herbal compounds, and elaborate detailed mechanisms of their efficacy in regulating cardiac ion channels and in alleviating arrhythmia and CVD. We also address current limitations and opportunities for developing new anti-CVD drugs based on Chinese herbal medicines.
ABC transporters are essential for cellular physiology. Humans have 48 ABC genes organized into seven distinct families. Of these genes, 44 (in five distinct families) encode for membrane transporters, of which several are involved in drug resistance and disease pathways resulting from transporter dysfunction. Over the last decade, advances in structural biology have vastly expanded our mechanistic understanding of human ABC transporter function, revealing details of their molecular arrangement, regulation, and interactions, facilitated in large part by advances in cryo-EM that have rendered hitherto inaccessible targets amenable to high-resolution structural analysis. As a result, experimentally determined structures of multiple members of each of the five families of ABC transporters in humans are now available. Here we review this recent progress, highlighting the physiological relevance of human ABC transporters and mechanistic insights gleaned from their direct structure determination. We also discuss the impact and limitations of model systems and structure prediction methods in understanding human ABC transporters and discuss current challenges and future research directions.
Expected final online publication date for the Annual Review of Biophysics, Volume 52 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Cantù syndrome (CS) is a rare multisystemic disorder, characterized by congenital hypertrichosis, macrocephaly, facial dysmorphisms, cardiomegaly, vascular, and skeletal anomalies. From the cognitive point of view, most of the patients show a mild speech delay and a few of them present intellectual disability and learning difficulties. To date, most CS‐reported cases are caused by heterozygous ABCC9 gene mutations. Only three patients with CS and heterozygous KCNJ8 gene variants have been reported. The authors here present the fourth case of CS with a variant in KCNJ8 in a 6‐month‐old baby. Diagnosis was reached through Trio‐Whole Exome analysis that revealed a de novo missense variant in KCNJ8.
Pattern hair loss (PHL) is the most frequent cause of hair loss in men and women, accounting for 65% of consultations in a hair referral center. PHL is understood to represent a hereditary, age-dependent progressive thinning of the scalp hair, which follows distinct clinical patterns with notable differences depending on sex and age of onset. Clinical and investigative advances have helped us to understand some of the pathogenic steps, leading to PHL. Besides genetic factors and peculiarities of androgen metabolism, additional pathogenic factors that are suspected include microbiomata, oxidative stress, and microinflammation. While further suspects are likely to be exposed, individual diversity of causal agents, as well as of the sequence of events, or combined factors, must be kept in mind. A large number of therapeutic molecules claimed to be active and patented in this field, and their limited efficacy in offering a definitive cure of PHL confirm the complexity of PHL. The aim of therapy is to retard progression of hair thinning and increase hair coverage of the scalp. As yet, two FDA-approved drugs are available for this purpose, oral finasteride, and topical solution of minoxidil. Variations in posology and formulation allow for an enhancement of patient comfort and treatment efficacy. Antiandrogen treatments in women with normal androgen levels have questionable efficacy while having health risks.
Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.
Hypertrichosis refers to the growth of hair, of an excessive amount and thickness, on any part of the body. It must be distinguished from hirsutism which is characterized by excess growth of hair in androgen-dependent areas on the upper lip, chin, chest, linea alba, thigh and axilla. Hypertrichosis may be localized or generalized, and congenital or acquired. Excess hair growth has a psychological impact on the child as well as the parents due to the cosmetic disfigurement it produces. Current treatment options are limited and not wholly satisfactory. Treatment should be customized according to the area, nature and amount of hair growth, age of the patient and personal preferences. In addition, when hypertrichosis occurs as a component of a syndrome, multidisciplinary management is required to address the associated systemic features. A detailed review of inherited generalized hypertrichosis is presented here with emphasis on clinical clues to identifying complex syndromes with multisystem involvement.
Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore‐forming subunits of ATP‐sensitive potassium (KATP) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self‐reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross‐sectional manner, we invited 35 individuals (1–69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age‐related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale‐2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults.
Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of underlying causal genes is crucial to understand how these loci influence birth weight, and links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritise candidate genes at GWAS loci. We examined the proximity of genes implicated in developmental disorders to birth weight GWAS loci, using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected, both when the developmental disorder gene is the nearest gene to the birth weight SNP and also examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic developmental disorders with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight which could not previously be classified as fetal or maternal due to insufficient statistical power.
Background and Objective
Activated potassium channels were found to be strongly correlated with gingival overgrowth (GO) phenotype as we reviewed syndromic hereditary gingival fibromatosis (HGF). Nevertheless, the functional roles of potassium channels in gingival fibrosis or gingival overgrowth remained uncovered. The aim of the present study was to explore the pathogenic role of aberrantly activated potassium channel in Hereditary Gingival Fibromatosis (HGF).
Methods
Gingival tissues were collected from 9 HGF patients and 15 normal controls. Expression of KCNQ1 was detected by immunohistochemistry. Gingival fibroblasts were isolated, and outward K⁺ currents were detected by whole‐cell patch‐clamp analysis, transmembrane potential was determined by flow cytometry. Normal human gingival fibroblasts (NHGFs) were transfected with KCNQ1 adenovirus or treated with KCNQ1 selective agonist ML277 and antagonist chromanol 293B. Accumulation of Extracellular Matrix (ECM) was measured by Western blotting and Sircol Soluble Collagen Assay. Content of secreted TGF‐β1 was measured by ELISA. Active RAS pull‐down assay and cell immunofluorescence were utilized to verify RAS activation.
Results
KCNQ1 was upregulated in gingival tissues derived from HGF patients and HGF gingival fibroblasts presented increased outward K⁺ currents than NHGFs. Overexpression of KCNQ1, or KCNQ1 agonist ML277, promoted fibrotic responses of NHGFs. TGF‐β1 and KCNQ1 channels formed a positive feed‐back loop. ML277 generated lateral clustering and activation of Ras on plasma membrane, followed by augmented MAPK/AP‐1 signaling pathway output. JNK or ERK1/2 inhibitors suppressed ML277‐induced AP‐1 and ECM upregulation.
Conclusion
Activation of KCNQ1 potassium channel promoted fibrogenic responses in NHGFs via Ras/MAPK/AP‐1 signaling.
Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.2/SUR1 complex. To characterize hit compounds, we developed an assay to quantify endogenous potassium channel activity in INS-1E cells. We quantified ligand-regulated potassium channel activity in INS-1E cells using fluorescence imaging and thallium flux. Potassium channel activity was metabolically regulated and coupled to insulin secretion. The pharmacology of channel opening agents (diazoxide) and closing agents (sulfonylureas) was used to validate the applicability of the assay. A precise high-throughput assay was enabled, and phenotypic screening hits were triaged to enable a higher likelihood of discovering chemical matter with novel and useful mechanisms of action.
Cantύ Syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe one CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying KATP channel subunits in gut smooth muscle, and to model the consequences of altered KATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle KATP channels throughout the small intestine and colon. Knock-in mice, carrying human KCNJ8 and ABCC9 CS mutations in the endogenous loci, exhibit reduced intrinsic contractility throughout the intestine, resulting in death when weaned onto solid food in the most severely affected animals. Death is avoided by weaning onto a liquid gel diet, implicating intestinal insufficiency and bowel impaction as the underlying cause, and GI transit is normalized by treatment with the KATP inhibitor glibenclamide. We thus define the molecular basis of intestinal KATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy.
The histological spectrum of the central fibrous body (CFB) of the heart, particularly in humans, is not fully characterized. Herein, we describe the presence of cartilage and bone within the CFB of 2 explanted heart specimens from patients with known mutation-driven cardiomyopathy involving the TNNI3 and TNNT2 genes, review the existing literature on the identified variants particularly TNNI3 (p.Asn185Thrfs*14) and TNNT2 (p.Arg141Trp), and provide insights into the plausible nature of such histopathological observation based on animal studies and the few reported cases in humans.
Background:
Diazoxide is widely used to manage congenital hyperinsulinism and is generally well tolerated. Pericardial effusion is not a recognized side effect of diazoxide, apart from 2 single case reports.
Case description:
Three patients with congenital hyperinsulinism developed pericardial effusion at the ages of 7 weeks, 8 months, and 17 years. The duration of diazoxide treatment (10-15 mg/kg/day) was 6.5 weeks, 5 months, and 17 years, respectively. There was no evidence of fluid overload or significant other cardiac anomaly. The 7-week-old patient presented with signs of cardiac failure, was treated with diuretics, and the effusion resolved after cessation of diazoxide. The 8-month-old patient required emergency subxiphoid drainage of the effusion due to hemodynamic compromise. The pericardial fluid had high numbers of polymorphonuclear cells, but did not grow any organisms, and histology showed non-specific chronic reactive changes; the effusion did not recur after cessation of diazoxide. The 17-year-old patient presented with atrial fibrillation, was treated with beta blockade and colchicine, and continues on diazoxide with monitoring of the effusion by ultrasound.
Conclusion:
Patients on long-term diazoxide treatment may be at risk of pericardial effusion, the timing and significance of which is unpredictable. The duration of diazoxide treatment before presentation of pericardial effusion varied in our patients from weeks to years. We advise serial echocardiography 1-2 months after commencement of diazoxide and annually thereafter.
Cantu syndrome is a rare condition which is characterized clinically by hypertrichosis, cardiomegaly and bone abnormalities. Inherited hypertrichoses are very rare human disorders whose incidence has been estimated as low as 1 in 1 billion. The genetic basis of hypertrichosis is largely unknown, and currently no single gene has been directly implicated in its pathogenesis, although position effects have been reported.
We analyzed the DNA of a patient with Cantu syndrome on the Affymetrix Cytogenetics Whole-Genome 2.7M array for copy number variations (CNVs). We then performed genomic copy number quantification using qPCR, and finally we performed gene expression analysis in the hair follicle for the genes lying within and around the region of the duplication.
We identified a 375 kb duplication on chromosome 4q26-27. The duplication region encompassed three genes, which included MYOZ2, USP53 and FABP2. MYOZ2 and USP53 are known to be highly expressed in the cardiac muscle, and we found that USP53 is expressed in the hair follicle.
We propose that CNVs involving chromosome 4q26-27 may be associated with Cantu syndrome. CNVs spanning several genes may help define the molecular basis of syndromes which have unrelated clinical features.
The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.
ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.
Unusually among ATP-binding cassette proteins, the sulfonylurea receptor (SUR) acts as a channel regulator. ATP-sensitive potassium channels are octameric complexes composed of four pore-forming Kir6.2 subunits and four regulatory SUR subunits. Two different genes encode SUR1 (ABCC8) and SUR2 (ABCC9), with the latter being differentially spliced to give SUR2A and SUR2B, which differ only in their C-terminal 42 amino acids. ATP-sensitive potassium channels containing these different SUR2 isoforms are differentially modulated by MgATP, with Kir6.2/SUR2B being activated more than Kir6.2/SUR2A. We show here that purified SUR2B has a lower ATPase activity and a 10-fold lower K(m) for MgATP than SUR2A. Similarly, the isolated nucleotide-binding domain (NBD) 2 of SUR2B was less active than that of SUR2A. We further found that the NBDs of SUR2B interact, and that the activity of full-length SUR cannot be predicted from that of either the isolated NBDs or NBD mixtures. Notably, deletion of the last 42 amino acids from NBD2 of SUR2 resulted in ATPase activity resembling that of NBD2 of SUR2A rather than that of NBD2 of SUR2B: this might indicate that these amino acids are responsible for the lower ATPase activity of SUR2B and the isolated NBD2 of SUR2B. We suggest that the lower ATPase activity of SUR2B may result in enhanced duration of the MgADP-bound state, leading to channel activation.
Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.
An important objective for inferring the evolutionary history of gene families is the determination of orthologies and paralogies. Lineage-specific paralog loss following whole-genome duplication events can cause anciently related homologs to appear in some assays as orthologs. Conserved synteny-the tendency of neighboring genes to retain their relative positions and orders on chromosomes over evolutionary time-can help resolve such errors. Several previous studies examined genome-wide syntenic conservation to infer the contents of ancestral chromosomes and provided insights into the architecture of ancestral genomes, but did not provide methods or tools applicable to the study of the evolution of individual gene families. We developed an automated system to identify conserved syntenic regions in a primary genome using as outgroup a genome that diverged from the investigated lineage before a whole-genome duplication event. The product of this automated analysis, the Synteny Database, allows a user to examine fully or partially assembled genomes. The Synteny Database is optimized for the investigation of individual gene families in multiple lineages and can detect chromosomal inversions and translocations as well as ohnologs (paralogs derived by whole-genome duplication) gone missing. To demonstrate the utility of the system, we present a case study of gene family evolution, investigating the ARNTL gene family in the genomes of Ciona intestinalis, amphioxus, zebrafish, and human.
Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K(ATP)) channels that adjust membrane potential-dependent functions to match cellular energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.
The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.
We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels.
We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.
Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.
The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.
Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (KATP) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are a common cause of neonatal diabetes mellitus. Here we investigate the molecular mechanism by which two heterozygous mutations in the second nucleotide-binding domain (NBD2) of SUR1 (R1380L and R1380C) separately cause neonatal diabetes. SUR1 is a channel regulator that modulates the gating of the pore formed by Kir6.2. KATP channel activity is inhibited by ATP binding to Kir6.2 but is stimulated by MgADP binding, or by MgATP binding and hydrolysis, at the NBDs of SUR1. Functional analysis of purified NBD2 showed that each mutation enhances MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and NBD2. Inhibition of ATP hydrolysis by MgADP was unaffected by mutation of R1380, but inhibition by beryllium fluoride (which traps the ATPase cycle in the prehydrolytic state) was reduced. MgADP-dependent activation of KATP channel activity was unaffected. These data suggest that the R1380L and R1380C mutations enhance the off-rate of Pi, thereby enhancing the hydrolytic rate. Molecular modeling studies supported this idea. Because mutant channels were inhibited less strongly by MgATP, this would increase KATP currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes.
• SUR1
• KATP channel
• ATP hydrolysis
• sulfonylurea receptor
Unusually among ATP-binding cassette proteins, the sulfonylurea receptor (SUR) acts as a channel regulator. ATP-sensitive potassium channels are octameric complexes composed of four pore-forming Kir6.2 subunits and four regulatory SUR subunits. Two different genes encode SUR1 (ABCC8) and SUR2 (ABCC9), with the latter being differentially spliced to give SUR2A and SUR2B, which differ only in their C-terminal 42 amino acids. ATP-sensitive potassium channels containing these different SUR2 isoforms are differentially modulated by MgATP, with Kir6.2/SUR2B being activated more than Kir6.2/SUR2A. We show here that purified SUR2B has a lower ATPase activity and a 10-fold lower Km for MgATP than SUR2A. Similarly, the isolated nucleotide-binding domain (NBD) 2 of SUR2B was less active than that of SUR2A. We further found that the NBDs of SUR2B interact, and that the activity of full-length SUR cannot be predicted from that of either the isolated NBDs or NBD mixtures. Notably, deletion of the last 42 amino acids from NBD2 of SUR2 resulted in ATPase activity resembling that of NBD2 of SUR2A rather than that of NBD2 of SUR2B: this might indicate that these amino acids are responsible for the lower ATPase activity of SUR2B and the isolated NBD2 of SUR2B. We suggest that the lower ATPase activity of SUR2B may result in enhanced duration of the MgADP-bound state, leading to channel activation.
In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (K(ATP)) channel activity provides a unique link between cellular energetics and electrical excitability. Over the past ten years, a steady drumbeat of crystallographic and electrophysiological studies has led to detailed structural and kinetic models that define the molecular basis of channel activity. In parallel, the uncovering of disease-causing mutations of K(ATP) has led to an explanation of the molecular basis of disease and, in turn, to a better understanding of the structural basis of channel function.
Cantú syndrome (CS) is characterized by congenital hypertrichosis, osteochondrodysplasia, cardiomegaly, and coarse facial appearance; autosomal recessive inheritance has been postulated. We report on a Mexican family with CS; the affected members are the 44-year-old father and his two children (a male and female), aged 14 and 4 years, respectively; each shows the classic characteristics, but the father and the brother also have a previously unreported feature, namely, a thick calvarium. This is the first reported instance of male-to-male transmission of CS. With the paternal age effect found in the reported sporadic cases and the segregation analysis [Robertson et al., 1999], autosomal dominant inheritance is more likely than autosomal recessive inheritance. The cases of affected sibs reported by Cantú et al. [1982] could be explained by parental gonadal mosaicism. Am. J. Med. Genet. 94:421–427, 2000. © 2000 Wiley-Liss, Inc.
Cantú syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare condition, previously reported in 13 patients. We report on two additional patients with this disorder. One of the patients had pulmonary hypertension of unknown cause which was responsive to steroid therapy. She also had unusual, deep plantar creases, not reported previously in Cantú syndrome. Autosomal recessive inheritance has been suggested previously on the basis of sib recurrence in one family and consanguinity in another. We have performed a segregation analysis based on all reported families to date; the data indicate autosomal recessive inheritance is unlikely. A new dominant mutation or microdeletion syndrome are more likely possibilities, sib recurrence possibly representing gonadal mosaicism. Am. J. Med. Genet. 85:395–402, 1999. © 1999 Wiley-Liss, Inc.
We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding of its mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans. Minoxidil may also cause prolongation of anagen and increases hair follicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle. A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the application of results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. In this article we review the current state of knowledge on the mode of action of minoxidil on hair growth and indicate lines of future research.
Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.
In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca(2+) concentrations during each contraction and relaxation cycle. This review highlights a number of proteins that regulate signaling Ca(2+) in both normal and pathological conditions including cardiac hypertrophy and heart failure, and discusses how these pathways are not regulated by the marked elevation in free intracellular calcium ([Ca(2+) ](i)) during contraction but require smaller sustained increases in Ca(2+) concentration. In addition, we present published evidence that the pool of Ca(2+) that regulates signaling is compartmentalized into distinct cellular microdomains and is thus distinct from that regulating contraction.
Cantú syndrome, a rare disorder of congenital hypertrichosis, characteristic facial anomalies, cardiomegaly, and osteochondrodysplasia was first described in 1982 by Cantú. Twenty-three cases of Cantú syndrome have been reported to date. The pathogenesis of this rare autosomal dominant condition is unknown. We describe 10 patients with Cantú syndrome (9 new cases and the long-term follow-up of a 10th case reported by Robertson in 1999) comparing the phenotype with that of the previously reported cases. We describe how the distinctive facial appearance evolves with time and report several new findings including recurrent infections with low immunoglobulin levels and gastric bleeding in some of our patients. The cardiac manifestations include patent ductus arteriosus, septal hypertrophy, pulmonary hypertension, and pericardial effusions. They may follow a benign course, but of the 10 cases we report, 4 patients required surgical closure of the patent ductus arteriosus and 1 patient a pericardectomy. Long-term follow-up of these patients has shown reassuring neuro-developmental outcome and the emergence of a behavior phenotype including obsessive traits and anxiety.
The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.
Three female patients with Cantu syndrome were studied, two of whom were adults presenting with the complication of lymphoedema, as described earlier in a male patient with this syndrome. The aim of this study is to report the clinical characteristics of these three new cases and to emphasize that lymphoedema, as observed in two of the patients described here, has been observed in 11.5% of patients with Cantu syndrome and that heterochromia iridis, observed in one patient, is probably a new feature of this condition.
BRL 34915 [6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl) 2H-benzo(b) pyran-3-ol], minoxidil sulfate and diazoxide may relax vascular smooth muscle via hyperpolarization due to an opening of membrane potassium channels. We therefore examined the effects of several potassium channel antagonists on the relaxation response to these vasodilators in isolated rat portal venous strips which were mounted in vitro for detecting changes in isometric force. BRL 34915 (IC50 = 4.7 X 10(-8) M), minoxidil sulfate (IC50 = 1.4 X 10(-7) M) and diazoxide (IC50 = 5 X 10(-6) M) elicited concentration-dependent relaxations of the spontaneous, myogenic contractions in venous strips. The relatively nonselective potassium channel antagonists tetraethylammonium ion (0.3-10 X 10(-3) M) and 4-aminopyridine (1-10 X 10(-3) M) caused concentration-dependent shifts (5- to 50-fold) in the relaxation responses to each vasodilator. Charybdotoxin (up to 10(-7) M) and apamin (up to 10(-7) M), known to be antagonists of high and low conductance calcium-activated potassium channels, respectively, had no inhibitory effect on the relaxation-response curves to BRL 34915, minoxidil sulfate or diazoxide. Glyburide (10(-7) to 3 X 10(-5) M), a sulfonylurea which has been shown to block the ATP-modulated potassium channel in insulin-secreting cells, caused concentration-dependent shifts to the right (up to 100-fold) of the IC50 value for BRL 34915 and diazoxide, and at 10(-6) M, abolished the relaxation response to minoxidil sulfate.(ABSTRACT TRUNCATED AT 250 WORDS)
The mechanism of smooth muscle relaxing effect of minoxidil sulfate (MxSO4) was investigated in isolated rabbit superior mesenteric artery. MxSO4 (5 X 10(-6) M) was found to effectively relax maximal norepinephrine (NE; at 5 X 10(-6) M) contraction, but failed to relax 80 mM K+-induced contraction. MxSO4-induced relaxation was endothelium independent. When the tissues were exposed to increased extracellular K+ (10-25 mM), and then contracted with NE, the relaxation response to MxSO4 was significantly attenuated. Tetraethylammonium (5-10 mM) pretreatment caused pronounced inhibition of MxSO4-induced relaxation. Pretreatment with ouabain (0.5-5 microM) also significantly inhibited MxSO4 relaxation. This effect of ouabain was found to be due to its effect on K+ gradient. These data suggested a role of K+ permeability during MxSO4 relaxation which was further confirmed when it was found that MxSO4 can cause a significant stimulation of 42K efflux from the mesenteric artery preloaded with 42K. It is suggested that MxSO4 may act as a K+ channel agonist to affect the plasmalemmal Ca++ permeability during agonist activation. Consistent with this, MxSO4 was demonstrated to cause an inhibition of NE-stimulated 45Ca influx in this tissue. Such a strong dependence on K+ permeability makes MxSO4 a unique vasodilator among the clinically used vasodilators.
Two sibs and two other unrelated patients presented a distinct previously undescribed syndrome consisting of generalized congenital hypertrichosis, macrosomy at birth, narrow thorax, cardiomegaly, wide ribs, platyspondyly, hypoplastic ischiopubic branches, small obturator foramen, bilateral coxa valga, enlarged medullar canal, long bones shaped like an ‘Erlenmeyer flasks’ and generalized osteopenia. The family data suggest autosomal recessive inheritance.
Minoxidil was found to inhibit the proliferation of smooth muscle cells in the proliferating phase, but not in the quiescent phase. Treatment of proliferating or quiescent cells with minoxidil resulted in a dose- and time-dependent stimulation of elastin synthesis specifically. Maximum stimulation (fourfold) occurred in cells treated with 1 mM minoxidil for 48 h. The stimulation of elastin synthesis was accompanied by a proportional increase in elastin mRNA level, and it was partially prevented by a K+ channel blocker (tetraethylammonium) and completely prevented by high K+ salt (0.1 M). Minoxidil had no significant effect on the extent of prolyl hydroxylation in newly synthesized elastin. These results indicate that minoxidil stimulates elastin synthesis at a pretranslational level by a mechanism unrelated to cell proliferation but one that may involve K+ efflux. As a pharmacological agent capable of stimulating elastin expression, minoxidil would be a useful drug for the treatment of abnormal elastin metabolism.
The hypertrichosis and osteochondrodysplasia syndrome is a rare entity with clinical findings including macrosomia at birth cardiomegaly. Autosomal recessive inheritance is presumed based on the report of two affected sibs born to healthy parents. Here we report on four new patients with their follow-up data, as well as on one of the four cases from the original report. Comparison of all eight cases indicates that they share 50% of clinical and radiological changes. This report contributes to the further delineation of this newly recognized syndrome.
Cantu syndrome is a rare condition whose main features are hypertrichosis, cardiac anomalies and wide ribs. Four children have been described and we now present details of a further three. The parents of one of these are first cousins, adding weight to Cantu's theory that the condition is an autosomal recessive disease.
Cantú syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare condition, previously reported in 13 patients. We report on two additional patients with this disorder. One of the patients had pulmonary hypertension of unknown cause which was responsive to steroid therapy. She also had unusual, deep plantar creases, not reported previously in Cantú syndrome. Autosomal recessive inheritance has been suggested previously on the basis of sib recurrence in one family and consanguinity in another. We have performed a segregation analysis based on all reported families to date; the data indicate autosomal recessive inheritance is unlikely. A new dominant mutation or microdeletion syndrome are more likely possibilities, sib recurrence possibly representing gonadal mosaicism.
Cantú syndrome (CS) is characterized by congenital hypertrichosis, osteochondrodysplasia, cardiomegaly, and coarse facial appearance; autosomal recessive inheritance has been postulated. We report on a Mexican family with CS; the affected members are the 44-year-old father and his two children (a male and female), aged 14 and 4 years, respectively; each shows the classic characteristics, but the father and the brother also have a previously unreported feature, namely, a thick calvarium. This is the first reported instance of male-to-male transmission of CS. With the paternal age effect found in the reported sporadic cases and the segregation analysis [Robertson et al., 1999], autosomal dominant inheritance is more likely than autosomal recessive inheritance. The cases of affected sibs reported by Cantú et al. [1982] could be explained by parental gonadal mosaicism.
ABC transporters form one of the largest of all protein families with a diversity of physiological functions. In Escherichia coli almost 5% of the genome is occupied by genes encoding components of these transporters, and there are examples in all species from microbes to man. In this overview, the importance of studies on bacteria in elucidating many basic principles pertaining to ABC transporters is emphasised. The family is described and a general overview of the structure and function of these transporters is presented.
Cantú syndrome consists of hypertrichosis, osteochondrodysplasia, and cardiomegaly, and has been reported in 18 patients to date. We report an infant with Cantú syndrome. In addition to typical findings, he had relatively mild radiological and cardiological manifestations. Previously undescribed findings included pyloric stenosis and elevated alkaline phosphatase levels. Brain scans showed bilateral calcification of the Arteriae thalamostriatae and widening of the outer liquor spaces and lateral ventricles. Because the propositus is the youngest patient reported to date, our findings refine the clinical spectrum of Cantú syndrome in neonates and young infants. The etiology and mode of inheritance of Cantú syndrome are unknown. Most cases are sporadic. Microdeletions have been discussed as a possible cause of Cantú syndrome. Recently, several syndromes with multiple congenital anomalies and mental retardation have been shown to be caused by subtelomeric chromosome aberrations. We excluded the presence of a cryptic subtelomeric chromosome anomaly in our patient by fluorescence in situ hybridization (FISH) screening with locus-specific probes.
Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8
billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy
with refractory congestive heart failure is caused by a dominant Arg → Cys missense mutation at residue 9 (R9C) in phospholamban
(PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+–adenosine triphosphatase (SERCA2a) pump. Transgenic PLNR9C mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type
PLN, PLNR9C did not directly inhibit SERCA2a. Rather, PLNR9C trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of
calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure—a
finding that may lead to therapeutic opportunities.
Three new studies examine how a regulator of calcium homeostasis contributes to heart failure in humans and mice.
Openers of ATP-sensitive K+ channels (KATP channels) are thought to act by enhancing the ATPase activity of sulphonylurea receptors (SURs), the regulatory channel subunits. At higher concentrations, some openers activate KATP channels also in the absence of MgATP. Here, we describe binding and effect of structurally diverse openers in the absence of Mg2+ and presence of EDTA.
Binding of openers to SUR2B was measured using a mutant with high affinity for [3H]glibenclamide ([3H]GBC). In the absence of Mg2+, ‘typical' openers (benzopyrans, cyanoguanidines and aprikalim) inhibited [3H]GBC binding with Ki values ∼200 × higher than in the presence of MgATP. Minoxidil sulphate and nicorandil were inactive, whereas binding of diazoxide was unaffected by MgATP.
In the absence/presence of MgATP, N-cyano-N′-(1,1-dimethylpropyl)-N″-3-pyridylguanidine (P1075) activated the Kir6.2/SUR2B channel in inside–out patches with EC50=2000/67nM and Emax=32/134%. In the absence of Mg2+, responses were variable with only a small part of the variability being explained by a decrease in channel responsiveness with time after patch excision and to differences in the ATP sensitivity between patches.
The rank order of efficacy of the openers was P1075>rilmakalim ∼nicorandil>diazoxide>minoxidil sulphate.
The data show that structurally diverse openers are able to bind to, and to activate the Kir6.2/SUR2B channel by a pathway independent of ATP hydrolysis. These effects are observed at concentrations used to define the biochemical mechanism of the openers in the presence of MgATP and allow the openers to be classified into ‘typical’ and ‘atypical’ KCOs with diazoxide standing apart.
British Journal of Pharmacology (2003) 139, 368–380. doi:10.1038/sj.bjp.0705238
We report on a 16-year-old boy with a distal 1p36 deletion with some clinical features consistent with Cantu syndrome (OMIM#239850). He also has hypercholesterolemia, type II diabetes, recurrent bony fractures, and non-alcoholic steatohepatitis, not previously described in either condition. The 1p36 deletion was detected in a screen of all chromosome subtelomeres using multiplex ligation-dependent probe amplification and was verified using FISH with a region-specific BAC clone. We suggest that patients suspected of having Cantu syndrome, especially those with unusual or more severe manifestations be analyzed for distal 1p36 deletions.
Cantu syndrome, or hypertrichosis-osteodysplasia-cardiomegaly syndrome, is a rare disorder of unknown etiology, associated with hypertrichosis, characteristic facial features, skeletal abnormalities, cardiomegaly, and occasional pericardial effusions. Although autosomal recessive inheritance was originally proposed, a man with three affected children has been reported, making autosomal dominant inheritance likely. We report on a woman and her two daughters with Cantu syndrome, further confirming dominant inheritance. All three of our patients have cardiac involvement, and symptomatic pericardial effusions requiring surgical intervention occurred in the mother and one of her daughters. Chromosome microarray analysis was normal in one of the girls. The etiology of the cardiomegaly and pericardial effusions in Cantu syndrome is unknown. We review all previously reported cases of Cantu syndrome and the associated cardiac manifestations.
Web Resources The URLs for data presented herein are as follows: Database of Genomic Variants, http://projects.tcag.ca/variation/ DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources)
- Accepted
Accepted: April 20, 2012 Published online: May 17, 2012 Web Resources The URLs for data presented herein are as follows: Database of Genomic Variants, http://projects.tcag.ca/variation/ DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources), http://decipher.sanger. ac.uk/ Exome Variant Server, NHLBI Exome Sequencing Project (ESP), http://evs.gs.washington.edu/EVS/ Online Mendelian Inheritance in Man (OMIM), http://www. omim.org UCSC Genome Browser, http://genome.ucsc.edu/ References
Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: further delineation of a new genetic syndrome
- Garcia-Cruz