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A, Whole chromosome 17 view of the array-CGH profile of patient 8. The arrow points to the 3-Mb deletion in the band 17q24.2q24.3 (GRCh37/h19). B, Ideogram of chromosome 17 (top) with the genes included in the locus 64 298 926 to 68 750 000 bp of the 17q24.2q24.3 band (GRCh37/h19). The black blocks represent the size and position of the deletions in 2 different scales. Scale 1, deletions 20 kb (cases 1, 3, 4, 7, 8, and 10) (Stewart et al) and scale 2, deletions 20 kb (case 2, 5, 6, 9, and 11). C, FISH analysis array-CGH result confirmation: upper panel, control male; lower panel, patient 7. The arrow points to the existing PRKAR1A copy (the probe cross-hybridizes with chromosome 6). D, Average relative PRKAR1A mRNA levels (Ct) in peripheral lymphocytes, using ACTB as an endogenous control. The differences between patient and control samples are statistically significant with a P value of .02. Patients included cases 3, 7, 8, 9, and 5; a total of 5 samples from age-and gender-matched individuals were used as controls. (A full and detailed description of case 12 can be found in Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J, Boland JF, Burdette LA, Brown C, Gatti RA, Alter BP, Biesecker LG, Savage SA, unpublished data.)
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Background:
Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systemat...
Contexts in source publication
Context 1
... patients had deletions of the 17q24.2-q24.3 locus where the PRKAR1A gene is located ( Figure 1A). For these experiments, a customized platform was designed to ob- tain an increased coverage of the PRKAR1A gene and its flanking regions, allowing at the same time the identifica- tion of small deletions involving one or a few exons. ...
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... these experiments, a customized platform was designed to ob- tain an increased coverage of the PRKAR1A gene and its flanking regions, allowing at the same time the identifica- tion of small deletions involving one or a few exons. The first and the last abnormal probes during the CGH and according to human genome build 19 (GRCh37/h19) were taken into account to calculate the deletion position and size ( Figure 1A). The size of the deletions varied from 328 bp to 3 Mb ( Figure 1B). ...
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... first and the last abnormal probes during the CGH and according to human genome build 19 (GRCh37/h19) were taken into account to calculate the deletion position and size ( Figure 1A). The size of the deletions varied from 328 bp to 3 Mb ( Figure 1B). In 5 of the 11 cases, the size of the deletion exceeded 1 Mb and included up to 20 known genes ( Figure 1B). ...
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... size of the deletions varied from 328 bp to 3 Mb ( Figure 1B). In 5 of the 11 cases, the size of the deletion exceeded 1 Mb and included up to 20 known genes ( Figure 1B). FISH confirmed the abnormal- ...
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... qPCR was performed to calculate the relative PRKAR1A mRNA levels compared with -actin (ACTB) as an endogenous control. Figure 1D shows the average relative mRNA levels from 4 of 11 cases (patients 3, 7, 8, and 9) whose material was available. Expression of the PRKAR1A gene in these 4 cases is compared with the average relative mRNA levels from 5 age-and gender-matched control sam- ples (age range 11-40 years). ...
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... Indeed, in 5 of the 11 cases studied here, the deletion was larger than 1 Mb, and in some cases, the missing segment of DNA included up to 20 coding genes ( Figure 1B). The inclusion of PRKAR1A in all cases, even in the smallest deletion (328 bp), confirms the role of this gene in CNC (3, 8 -16), but we may assume at this point that most of the non-CNC manifestations in our patients are related to other genes in the 17q24.2- ...
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... some of the patients with 17q24.2-q24.3 deletions, the whole copy of the PRKAR1A gene was eliminated, and as expected, mRNA levels were lower ( Figure 1D), confirm- ing haploinsufficiency. Almost half of the patients, how- ever, had a partial deletion of the PRKAR1A gene (cases 2, 5, 6, 9, and 11); when available material was studied in some of these patients, the gene expression was signifi- cantly lower compared with control samples ( Figure 1D). ...
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... the whole copy of the PRKAR1A gene was eliminated, and as expected, mRNA levels were lower ( Figure 1D), confirm- ing haploinsufficiency. Almost half of the patients, how- ever, had a partial deletion of the PRKAR1A gene (cases 2, 5, 6, 9, and 11); when available material was studied in some of these patients, the gene expression was signifi- cantly lower compared with control samples ( Figure 1D). Patients 6 and 9 had a deletion that spanned only exon 1 of the PRKAR1A gene; material was available for study only from patient 9, and he, too, had lower expression of the gene. ...
Similar publications
We experienced a diagnostically challenging case of Carney complex (CNC). A 24-year-old woman had a past history of surgical removal of multiple cutaneous tumors in the childhood. She was followed as a patient of neurofibromatosis type 1 (NF1) and referred to our hospital for further treatment after she grew up to adulthood. At our hospital, severa...
Citations
... Acromegaly usually has a slowly-progressive course, and in most cases, it appears no earlier than 30 years old [52]. There is a phenotype-genotype correlation depending on the type of mutation of the PRKAR1A locus, where larger deletions may lead to a more severe phenotype [60,61]. Since these patients do not always carry an obvious PitNET, surgery may not always be a treatment option. ...
Pituitary neuroendocrine tumors (PitNETs), the third most common intracranial tumor, are mostly benign. However, some of them may display a more aggressive behavior, invading into the surrounding structures. While they may rarely metastasize, they may resist different treatment modalities. Several major advances in molecular biology in the past few years led to the discovery of the possible mechanisms involved in pituitary tumorigenesis with a possible therapeutic implication. The mutations in the different proteins involved in the Gsa/protein kinase A/c AMP signaling pathway are well-known and are responsible for many PitNETS, such as somatotropinomas and, in the context of syndromes, as the McCune–Albright syndrome, Carney complex, familiar isolated pituitary adenoma (FIPA), and X-linked acrogigantism (XLAG). The other pathways involved are the MAPK/ERK, PI3K/Akt, Wnt, and the most recently studied HIPPO pathways. Moreover, the mutations in several other tumor suppressor genes, such as menin and CDKN1B, are responsible for the MEN1 and MEN4 syndromes and succinate dehydrogenase (SDHx) in the context of the 3PAs syndrome. Furthermore, the pituitary stem cells and miRNAs hold an essential role in pituitary tumorigenesis and may represent new molecular targets for their diagnosis and treatment. This review aims to summarize the different cell signaling pathways and genes involved in pituitary tumorigenesis in an attempt to clarify their implications for diagnosis and management.
... Carney Complex is a multi-system disorder that shows both variable penetrance and variable expressivity (i.e., varying clinical manifestations, sometimes called pleiotropy) among affected individuals. The manifestations of Carney Complex include hyperplasia/adenomas of the cortex of the adrenal gland, cardiac and other myxomas, spotty skin pigmentation (lentiginosis), and as well as numerous other abnormalities (51,(90)(91)(92)(93). Carney Complex is caused by germline mutations in PRKAR1A (which encodes the PKA regulatory RIa subunit) and, rarely, PRKACA or PRKACB [which encode the PKA catalytic subunits Ca or Cb, respectively, Figures 1, 2, refs (94)(95)(96)]. Germline/mosaic mutations in PRKACA or PRKACB also cause a complex congenital malformation syndrome, including some unusual tumors, that is phenotypically distinct from Carney complex (97). ...
... However, rare Carney Complex mutations are found in the catalytic Ca or Cb subunits (encoded by PRKACA or PRKACB, respectively). The PRKAR1A mutations in Carney Complex activate PKA by attenuating the abundance or action of the regulatory subunit (94,95,119). The majority of PRKAR1A mutations reduce the abundance of PRKAR1A mRNA by triggering nonsensemeditated mRNA decay, leading to haploinsufficiency (120). ...
The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly wide range of cell origins, clinical manifestations, and potential therapeutic options. Mutations in at least 9 cAMP signaling pathway genes ( TSHR, GPR101, GNAS, PDE8B, PDE11A, PRKARA1, PRKACA, PRKACB , and CREB ) have been identified as driver mutations in human cancer. Although all cAMP-signaling pathway cancers are driven by mutation(s) that impinge on a single signaling pathway, the ultimate tumor phenotype reflects interactions between five critical variables: (1) the precise gene(s) that undergo mutation in each specific tumor type; (2) the effects of specific allele(s) in any given gene; (3) mutations in modifier genes (mutational “context”); (4) the tissue-specific expression of various cAMP signaling pathway elements in the tumor stem cell; and (5) and the precise biochemical regulation of the pathway components in tumor cells. These varying oncogenic mechanisms reveal novel and important targets for drug discovery. There is considerable diversity in the “druggability” of cAMP-signaling components, with some elements (GPCRs, cAMP-specific phosphodiesterases and kinases) appearing to be prime drug candidates, while other elements (transcription factors, protein-protein interactions) are currently refractory to robust drug-development efforts. Further refinement of the precise driver mutations in individual tumors will be essential for directing priorities in drug discovery efforts that target these mutations.
... As a result, the amount of RIa protein produced is half of the normal amount (107-109). Large chromosomal deletions involving the PRKAR1A gene, even though rare, have also been identified (110,111). Occasionally, the pathogenic variant (missense, short in-frame insertions/deletions and splice variants) may lead to the production of an abnormal protein that is incapable of responding appropriately to cAMP levels or properly bind to the PKA catalytic subunits (108, 112). ...
Adrenal cortex produces glucocorticoids, mineralocorticoids and adrenal androgens which are essential for life, supporting balance, immune response and sexual maturation. Adrenocortical tumors and hyperplasias are a heterogenous group of adrenal disorders and they can be either sporadic or familial. Adrenocortical cancer is a rare and aggressive malignancy, and it is associated with poor prognosis. With the advance of next-generation sequencing technologies and improvement of genomic data analysis over the past decade, various genetic defects, either from germline or somatic origin, have been unraveled, improving diagnosis and treatment of numerous genetic disorders, including adrenocortical diseases. This review gives an overview of disorders associated with the adrenal cortex, the genetic factors of these disorders and their molecular implications.
... Most of the CNC variants that have been identified in PRKAR1A cause loss-of-function mutations such as frameshifts and stop gains (see Mineo et al. (2016) for example), whereas reports of large structural variations such as deletions of >1 kb are rare (Horvath et al., 2008;Salpea et al., 2014). Recently, comprehensive genomic profiling (CGP) has been widely applied to cancer, and some of the CGP panels, such as FoundationOne CDx (Hellmann et al., 2018), include PRKAR1A as a target gene. ...
... The first report of a large deletion in PRKAR1A being responsible for CNC was by Horvath et al., in 2008(Horvath et al., 2008. The same group reported other large deletions associated with CNC, but there was no familial cases in their cohort (Salpea et al., 2014). Iwata et al. described a single 0.5-Mb deletion involving the entire gene sequence of PRKAR1A shared by a mother and two of her offspring (Iwata et al., 2015). ...
... Thus, most CNC type 1 cases caused by inactivation of the germline PRKAR1A should be detectable by CGP panels that include the gene (for example, see Mineo et al. (2016)). However, in suspected cases of CNC with no common pathogenic variants in PRKAR1A, it is recommended that the potential for large deletions in the locus be investigated (Salpea et al., 2014;Stelmachowska-Banas et al., 2017). Our results indicated that the precise clinical diagnosis of CNC is critically dependent on histopathologic results, clinical symptoms and signs, and selection of an appropriate modality to detect structural variants in PRKAR1A in the absence of small nonfunctional variants. ...
Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. Chromosome 2p16 and PRKAR1A on chromosome 17 are known susceptibility loci for CNC. Here we report a mother and son with CNC caused by an 8.57‐kb deletion involving the transcription start site and non‐coding exon 1 of PRKAR1A. The proband is a 28‐year‐old male with bilateral large‐cell calcified Sertoli cell testicular tumors and pituitary adenoma. Comprehensive genomic profiling for cancer mutations using Foundation One CDx failed to detect any mutations in PRKAR1A in DNA from the testicular tumor. Single‐nucleotide polymorphism array analysis of the proband’s genomic DNA revealed a large deletion in the 5′ region of PRKAR1A. Genomic walking further delineated the region an 8.57‐kb deletion. A 1.68‐kb DNA fragment encompassed by the deleted region showed strong promoter activity in a NanoLuc luciferase reporter assay. The patient’s mother, who is suffering from recurrent cardiac myxoma, a critical sign for CNC, carried an identical deletion. The 8.57‐kb deleted region is a novel lesion for CNC and will facilitate molecular diagnosis of the disease. There is an inherited deletion of PRKAR1A gene that causes Carney complex. The deletion involves the promoter and non‐coding first exon of the PRKAR1A gene.
... Превалирующее число мутаций представлено заменой нуклеотида, делециями, вставками или комбинированными изменениями, включающими до 15 нуклеиновых кислот, однако в определенных работах, в частности Salpea и соавт. и Horvath и соавт., также описаны случаи и более крупных, хромосомных делеций у 11 и 2 неродственных пациентов с комплексом Карни соответственно [20,22,23]. ...
Micronodular adrenal hyperplasia is a rare cause of ACTH-independent Cushing syndrome. It can be divided into two entities: primary pigmented nodular adrenocortical disease (PPNAD) and non-pigmented micronodular adrenocortical disease, among which familial and sporadic forms are distinguished. The most common is the genetically determined familial form PPNAD, as one of the components of Carney complex. The vast majority of patients have identifiable pathogenic variants in the PRKAR1A gene. In addition to the PRKAR1A gene mutations, inactivating mutations in the genes encoding phosphodiesterases ( PDE11A4 and PDE8B ), as well as PRKACA gene amplification, have been described in individuals with isolated forms. Despite the relative antiquity of the description of micronodular adrenal hyperplasia and the Carney comlex, a detailed study of pathophysiological mechanisms, genetic and clinical aspects of this pathology, nowadays, clinicians continue to face «atypical» cases. Thus, the nature of this disease is not well understood and requires further research. This review presents the accumulated data on micronodular adrenal hyperplasia, genetics aspects, and also describes 2 unique clinical cases of isolated PPNAD with unilateral adrenalectomy results.
... Approximately 80% of pathogenic PRKAR1A variants are subject to mRNA nonsense-mediated decay of the mutant sequence and predicted absence of mutant protein products in affected cells. [2,[9][10][11]. Tumors from patients with CNC exhibit germline mutations and subsequent loss of heterozygosity at the PRKAR1A locus through a "second-hit" mutation, although haploinsufficiency of PRKAR1A may be sufficient for the early development of certain tumors [12,13]. Additionally, in patients with germline PRKAR1A defects and relatively large adrenocortical adenomas that developed in the background of PPNAD, somatic defects in the beta-catenin gene (CTNNB1) have been identified in the tumors only [14]. ...
Context
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC) a rare, autosomal dominant, multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating PRKAR1A defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease.
Case Description
A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal CT showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5 centimeter pigmented adenoma. DNA analysis by Sanger sequencing revealed two different PRKAR1A variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C>T and c.974-2A>G. “Deep” NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C>T variant, suggesting low-level mosaicism for this defect.
Conclusions
We present a case of PPNAD due to low-level mosaicism for a PRKAR1A defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic, PRKAR1A mutation. The identification of mosaicism for PRKAR1A, depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with PRKAR1A mosaicism, PPNAD, and an adenoma forming due to complete inactivation of PRKAR1A in adrenal tissue from a second, somatic only, coding sequence mutation.
... Вважається, що кардіальні міксоми виникають із субендотендокардіальних мезенхімальних мультипотентних клітин-попередників. Комплекс Карнея виникає внаслідок мутацій у гені PRKAR1A, який кодує регуляторну субодиницю протеїнкінази А R1α [58]. PRKAR1A може грати роль гена-пухлинного супресора, регулюючи активність протеїнкінази А, що у свою чергу може стимулювати або пригнічувати ріст і диференціювання клітин. ...
Медико-соціальне значення ендокринних орфанних захворювань обумовлено труднощами в діагностиці та лікуванні, а також несприятливим прогнозом і високою частотою інвалідизації пацієнтів із цією патологією. Особливо це стосується таких захворювань, як акромегалія та множинна ендокринна неоплазія. В Європі існує спеціальна програма, яка направлена на вирішення різноманітних питань щодо діагностики, лікування та соціального забезпечення пацієнтів з орфанними захворюваннями. Європейський проект «Орфанет» підтримується державними структурами, об’єднує інформацію щодо рідкісних захворювань практично у всіх європейських країнах і включає європейські, інтернаціональні, національні та регіональні реєстри орфанних захворювань. В Україні опубліковано Наказ Міністерства охорони здоров’я (МОЗ) України від 27.10.2014 р. № 778 «Про затвердження переліку рідкісних (орфанних) захворювань», яким офіційно затверджено 302 нозології, що віднесені до рідкісних захворювань. Серед орфанних захворювань вказано 61 рідкісну ендокринну хворобу (зокрема, розлади харчування та порушення обміну речовин), а також природженівади розвитку, хромосомні аномалії та рідкісні новоутворення, у визначенні тактики ведення яких лікар-ендокринолог бере безпосередню участь. Останнім часом зростає частота виявлення орфанних захворювань, зокрема і ендокринних. Причиною цього може бути покращення методів інструментальної та лабораторної діагностики, використання генетичних методів діагностики та більш широка обізнаність лікарів різних спеціальностей щодо ранніх проявів орфанних захворювань. В Україні проблема орфанних захворювань тривалий час перебувала в інертному стані. Ініціація ухвалення Національної стратегії з профілактики, діагностики та лікування рідкісних (орфанних) захворювань в Україні свідчить про визнання проблеми на державному рівні та дає можливість вирішення питань своєчасного виявлення і лікування рідкісних захворювань, а також забезпечення пацієнтів життєво необхідними лікарськими засобами.
... Subjects with ACRDYS1 have specific PRKAR1A mutations (Linglart et al. 2011). Subjects with 17q22-24 deletions that include the PRKAR1A gene also were described with a variety of skeletal abnormalities (Salpea et al. 2014). PRKACA defects were identified in isolated PPNAD, CPAs and other adrenocortical tumors (Beuschlein et al. 2014, Di Dalmazi et al. 2014, Carney et al. 2015, Lodish et al. 2015 and cardiac myxomas (Tseng et al. 2017, Stratakis 2018, as well as a variety of other neoplasms, including fibrolamellar hepatocellular carcinoma (Honeyman et al. 2014) and intraductal oncocytic papillary neoplasms of the pancreas and bile duct (Singhi et al. 2020). ...
Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.
... Carney complex (CNC) is an infrequent autosomal dominant syndrome of multiple endocrine neoplasia (adrenal, testicular, pituitary and thyroid tumors) and cardiocutaneous manifestations (lentiginosis, myxomas, nevi), with full penetrance [63,64]. Most cases are caused by de novo, loss-of-function mutations or deletions in the PRKAR1A gene; defects in PRKACB and 2p16 have also been described [65][66][67][68][69]. Up to 80% of CNC patients display subclinical GH excess, but clinically evident acromegaly is rare (12% of patients), and twothirds of CNC patients have co-existent mild hyperprolactinemia [63,70]. ...
Introduction: Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies.
Areas covered: This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized.
Expert opinion: Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients’ outcomes.
... Вважається, що кардіальні міксоми виникають з субендотендокардіальних мезенхімальних мультипотентних клітинпопередників. Комплекс Карнея виникає внаслідок мутацій у гені PRKAR1A, який кодує регуляторну субодиницю протеїнкінази А R1α [53]. PRKAR1A може відігравати роль гена -пухлинного супресора, регулюючи активність протеїнкінази А, що, у свою чергу, може стимулювати або пригнічувати ріст і диференціювання клітин. ...
Медико-социальное значение орфанных заболеваний обусловлено трудностями в диагностике и лечении, а также неблагоприятным прогнозом и высокой частотой инвалидизации пациентов. Принятие Национальной стратегии по профилактике, диагностике и лечению орфанных заболеваний в Украине свидетельствует о признании проблемы на государственном уровне и дает возможность решения вопросов своевременного выявления редких заболеваний, лечения и обеспечения пациентов жизненно необходимыми лекарственными средствами.
