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Photographs of the two patients. (a) Facial appearance of patient III.1 at the age of 29 years. Note microphthalmia of the right eye, long narrow face, microcephaly, large anteverted ears, bulbous nose, maxilla hypoplasia, and prognathism. (b) Facial view of patient III.8 at the age of 4 years. He also shows microphthalmia of the right eye, microcephaly, and a bulbous nose. Note the rounded face at young age that has also been described for other patients with PQBP1 mutations.
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X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of...
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... examination, the occipitofrontal circumference (OFC) was 46.5 cm (À6 SD). He also presented microphthalmia of the right eye and choroid coloboma of the left eye, spastic diplegia, campto- dactyly, and arachnodactyly; his ears are large, simple, and protruding ( Figure 2a). Numerous laboratory tests includ- ing biochemical analyses (of haemoglobin, copper, cerulo- plasmin, uric acid, etc.) turned out to be normal. ...
Citations
... The families carrying PQBP1 mutations were clinically similar to Renpenning syndrome [58]. Subsequently, a number of other research groups confirmed the genetic linkage between PQBP1 and intellectual disability [59][60][61][62][63][64][65][66]. This included other intellectual disability syndromes, such as Golabi-Ito-Hall syndrome [64], Hamel syndrome, Proteus syndrome, and Sutherland-Haan syndrome, which led to the concept of the Renpenning syndrome spectrum [61,67]. ...
The idea that a common pathology underlies various neurodegenerative diseases and dementias has attracted considerable attention in the basic and medical sciences. Polyglutamine binding protein-1 (PQBP1) was identified in 1998 after a molecule was predicted to bind to polyglutamine tract amino acid sequences, which are associated with a family of neurodegenerative disorders called polyglutamine diseases. Hereditary gene mutations of PQBP1 cause intellectual disability, whereas acquired loss of function of PQBP1 contributes to dementia pathology. PQBP1 functions in innate immune cells as an intracellular receptor that recognizes pathogens and neurodegenerative proteins. It is an intrinsically disordered protein that generates intracellular foci, similar to other neurodegenerative disease proteins such as TDP43, FUS, and hnRNPs. The knowledge accumulated over more than 20 years has given rise to a new concept that shifts in the equilibrium between physiological and pathological processes have their basis in the dysregulation of common protein structure-linked molecular mechanisms.
... Authors showed two male relatives who had a deletion in PQBP1 gene, and one of them had seizures, which was rarely described in previous cases (8). The first case related to an 18-year-old female was also reported (9). ...
... Epilepsy in children with mutation in the PQBP1 gene appears to be the exception rather than the rule since Stevenson et al. (5) found seizures reported in 11% of affected males. Another patient who had epilepsy had the same mutation as our patient and associated microphthalmia (8). In our patient, Thin posterior part of the corpus callosum (7) and nodular gray matter heterotopia [6] had pathological findings on brain MRI associated with a mutation in the PQBP1 gene. ...
Introduction: In 1962, Renpenning et al. published an article with 20 male patients from three generations with mental retardation. Scientists suggested that the syndrome with mutation mapped to the locus Xp11.2-p11.4 should be called Renpenning syndrome. The deletion/duplication of an AG dinucleotide on proximal Xp in the polyglutamine tract-binding protein 1 (PQBP1) gene causing frameshift in the fourth coding exon was identified as the most frequent mutation in this syndrome. Renpenning syndrome with asymmetric cerebellar hemispheres has not been reported previously. Case Presentation: In this case report, we presented an 11-year-old male with mild developmental delay and mild intellectual disability, microcephaly, dysmorphic face, short stature, and seizures. The following morphological abnormalities were detected: a wide nasal bridge, midfacial hypoplasia, short philtrum, low-set ears, low hanging columella, high palate, and narrow face. Neurological examination showed upper and lower extremities hypotonia with joint hypermobility. The patient had his first seizure at the age of seven, and he experienced a total of 10 seizures by the age 11. A systolic murmur of intensity 2/6 was present, and echocardiography showed chordae tendineae abnormalities in the left ventricle. Brain magnetic resonance imaging (MRI) showed asymmetric cerebellar hemispheres (mild right cerebellar hemisphere hypoplasia). A frameshift mutation in the polar reach domain (PRD) of the PQBP1 gene (c.459-462 delAGAG) was detected by exome sequencing. Conclusions: We showed the first case of genetically confirmed Renpenning syndrome in Serbia. Our patient had classical clinical manifestations for Renpenning syndrome as a consequence of frameshift mutation in the PRD of the PQBP1 gene. To the best of our knowledge, according to the literature, this is the first patient with Renpenning syndrome with asymmetric cerebellar hemispheres (mild right cerebellar hemisphere hypoplasia).
... Polyglutamine tract-binding protein 1 (PQBP1) has been directly linked to intellectual disability. Many studies have proven that mutations in PQBP1 (duplications or deletions of AG dinucleotides in the fourth coding exon) may be a primary cause of developmental deformities of the eyes (microphthalmia) and head (microcephaly) (Kleefstra et al., 2004;Martínez-Garay et al., 2007). Yang et al., 2020 analyzed the bone phenotype of Pqbp1-knockout mice (cKO) and found that Pqbp1-cKO mice exhibited brachycephaly and significant reduction in bone formation and chondrocytes. ...
Cavefish evolved a series of distinct survival mechanisms for adaptation to cave habitat. Such mechanisms include loss of eyesight and pigmentation, sensitive sensory organs, unique dietary preferences, and predation behavior. Thus, it is of great interest to understand the mechanisms underlying these adaptability traits of troglobites. The teleost genus Sinocyclocheilus (Cypriniformes: Cyprinidae) is endemic to China and has more than 70 species reported (including over 30 cavefish species). High species diversity and diverse phenotypes make the Sinocyclocheilus as an outstanding model for studying speciation and adaptive evolution. In this study, we conducted a comparative transcriptomics study on the brain tissues of two Sinocyclocheilus species (surface-dwelling species – Sinocyclocheilus malacopterus and semi-cave-dwelling species – Sinocyclocheilus rhinocerous living in the same water body. A total of 425,188,768 clean reads were generated, which contributed to 102,839 Unigenes. Bioinformatic analysis revealed a total of 3,289 differentially expressed genes (DEGs) between two species Comparing to S. malacopterus, 2,598 and 691 DEGs were found to be respectively, down-regulated and up-regulated in S. rhinocerous. Furthermore, it is also found tens of DEGs related to cave adaptability such as insulin secretion regulation (MafA, MafB, MafK, BRSK, and CDK16) and troglomorphic traits formation (CEP290, nmnat1, coasy, and pqbp1) in the cave-dwelling S. rhinocerous. Interestingly, most of the DEGs were found to be down-regulated in cavefish species and this trend of DEGs expression was confirmed through qPCR experiments. This study would provide an appropriate genetic basis for future studies on the formation of troglomorphic traits and adaptability characters of troglobites, and improve our understanding of mechanisms of cave adaptation.
... Although several genes identified in animal studies are critical for optic fissure closure during eye development, very few are known to cause coloboma in humans (Brown et al., 2009;. On the other hand, reports of human mutations are often not complemented by experimental mechanistic evidence either in animal models or in cell culture (Bourchany et al., 2015;Chassaing et al., 2016;Graham et al., 2003;Kahrizi et al., 2011;Martinez-Garay et al., 2007;Ng et al., 2012;Wenger et al., 2014). In many cases, studies on coloboma genetics have focused on a select number of genes, and many have included syndromic conditions with severe ocular phenotypes (e.g., severe microphthalmia and anophthalmia; Gonzalez-Rodriguez et al., 2010;Guo, Dai, Huang, Liao, & Bai, 2013;Mihelec et al., 2009;Morrison et al., 2002;Schimmenti et al., 2003;X. ...
Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high‐throughput screening of 38 known coloboma‐associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand‐binding domain, was a missense change in the highly conserved DNA‐binding domain predicted to affect the protein's DNA‐binding ability. In vitro studies revealed lower steady‐state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild‐type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA‐binding domain could result in human disease.
... Interestingly, patients with missense mutations including ours (patient 4) showed severe to profound ID (Lubs et al., 2006). The interfamilial and intrafamilial variability could be attributed to unknown modifier genes or epigenetic factors (Martínez-Garay et al., 2007) In conclusion, WES has helped in deciphering unrecognized phenotype of PQBP1-related disorders in a patient harboring missense mutation that differs substantially from those with truncating mutations. Thus, expanding the phenotypic spectrum of PQBP1. ...
We report two discordant clinical and imaging features in four male patients from two unrelated families of Egyptian descent with hemizygous pathogenic variants in PQBP1. The three patients of the first family displayed the typical features underlying PQBP1 such as the long triangular face, bulbous nose, hypoplastic malar region, and micrognathia, which were subsequently confirmed using targeted sequence analysis that showed a previously reported nonsense mutation c.586C>T p.R196*. Whole exome sequencing identified a novel missense PQBP1 variant c.530G>A:p.R177H in the second family, in which the index patient presented with intellectual disability and dysmorphic facial features reminiscent of Kabuki‐like syndrome and his brain magnetic resonance imaging revealed partial agenesis of corpus callosum, mild vermis, and brainstem hypoplasia. These imaging features are distinct from the previously described with a well‐known phenotype that is already known for PQBP1. This report expands the phenotypic spectrum of PQBP1‐related disorders and is the second reported missense PQBP1 variant. Further, it highlights the possible role of PQBP1 in hindbrain development.
... Renpenning syndrome R, Ch, OD 1 No [111] ...
Embryonic development of the vertebrate eye begins with the formation of an optic vesicle which folds inwards to form a double-layered optic cup with a fissure on the ventral surface, known as the optic fissure. Closure of the optic fissure is essential for subsequent growth and development of the eye. A defect in this process can leave a gap in the iris, retina or optic nerve, known as a coloboma, which can lead to severe visual impairment. This review brings together current information about genes and pathways regulating fissure closure from human coloboma patients and animal models. It focuses especially on current understanding of the morphological changes and processes of epithelial remodelling occurring at the fissure margins.
... Dans une revue de 2005, Stevenson et al.regroupent les cas publiés ce qui correspondait au total à 52 patients appartenant à dix familles(Stevenson et al. 2005). Depuis, 26 hommes atteints dans dix familles supplémentaires ont été rapportés (les délétions dans l'hexamère AG de l'exon 5 étant les mutations les plus récurrentes)(Fichera et al. 2002;Fichera et al. 2005;Cossée et al. 2006;Martínez-Garay et al. 2007;Rejeb et al. 2011;Germanaud et al. 2011). Le nombre de patients identifiés reste ainsi faible et ce malgré des caractéristiques cliniques désormais reconnaissables (mises en évidence notamment grâce à des revues abordant précisément les tableaux cliniques)(Kleefstra et al. 2004;Germanaud et al. 2011). ...
La déficience intellectuelle (DI) et les troubles du spectre autistique (ASD) sont deux troubles neurodéveloppementaux (NDD) présentant de nombreux chevauchements génétiques et phénotypiques ainsi qu’un biais de sexe important, avec plus de garçons atteints (1,4x plus pour la DI et 4x plus pour l'ASD). Au sein de notre laboratoire, le taux de diagnostic des patients souffrant de DI et/ou d’ASD est significativement plus élevé chez les filles que chez les garçons. De façon surprenante, nous n’avons pas observé de différence significative entre filles et garçons au niveau de la proportion de mutations pathogènes sur le chromosome X (5,3% versus 7,6%), confirmant ainsi que les mutations causales totalement pénétrantes sur ce chromosome ne peuvent pas expliquer la totalité de l’excès de garçons atteints de DI ou d'ASD. Nous avons donc choisi d’étudier une autre des hypothèses, plus environnementale, qui pourrait rendre le cerveau masculin plus susceptible au développement de NDD : le rôle des androgènes au cours du développement du cerveau. J'ai étudié l’effet de ces hormones masculines dans des précurseurs neuronaux humains (hNSCs) et observé que les androgènes augmentent la prolifération des hNSCs et les protègent contre la mort cellulaire en conditions stressantes. J'ai également mis en évidence que les androgènes, via leur récepteur (le récepteur aux androgènes), régulent une centaine de gènes dans les hNSCs avec, parmi eux, un enrichissement en gènes connus pour être différentiellement exprimés chez les individus avec ASD (dont NRCAM et FAM107A). La régulation de ces gènes par les androgènes pendant le développement du cerveau pourrait ainsi participer à la sensibilité accrue du cerveau masculin, exposé à d'autres facteurs génétiques et environnementaux, à développer une NDD.
... Defect of protein O-mannosylation may cause failure of neuronal migration in developing brain [19,20]; • PQBP1 that plays a role in transcription and alternative splicing associated with neurite outgrowth. PQBP1 is highly expressed in the CNS of embryonic or newborn rodents, with the peak around birth [21][22][23][24]; • SEN54, a tRNA splicing enzyme that causes pontocerebellar hypoplasia [25]; • SERA (D-3-phosphoglycerate dehydrogenase), which is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia [26,27]; • the transcription factor SOX11 that is implicated in the embryonic neurogenesis and in tissue modeling during development [28], as well as in the differentiation of granule cells to granule neurons [29]. ...
... Moreover, inspection of Table 1 reveals that five human proteins sharing peptides with ZIKV are also involved, when altered, in ocular anomalies such as microphthalmia, poor vision, nystagmus, retinal folding, retinal detachment, optic nerve hypoplasia, absence of retinal vessels, round areas of chorioretinal atrophy (GCP4) [30], optic atrophy (PCLO) [18], eye malformations, cystic retinal coloboma, cataract and anterior chamber synechia (POMT1) [19,20], microphtalmia and ocular colobomas (PQBP1) [23], and pediatric eye disorders (SOX11) [31,32]. These data appear of relevance in light of the reported association between ZIKV infection and ocular anomalies [33,34]. ...
Zika virus (ZIKV) infection during pregnancy ma be linked to fetal neurological complications that include brain damage and microcephaly. How the viral infection relates to fetal brain malformations is unknown. This study analyzes ZIKV polyprotein for peptide sharing with human proteins that when altered, associate with microcephaly and brain calcifications. Results highlight a vast viral versus human peptide commonality that, in particular, involves centriolar and centrosomal components canonically cataloged as microcephaly proteins, i.e., C2CD3, CASC5, CP131, GCP4, KIF2A, STIL, and TBG. Likewise, a search for ZIKV peptide occurrences in human proteins linked to Guillain-Barré-like syndromes also show a high, unexpected level of peptide sharing. Of note, further analyses using the Immune Epitope DataBase (IEDB) resource show that many of the shared peptides are endowed with immunological potential. The data indicate that immune reactions following ZIKV infection might be a considerable source of crossreactions with brain-specific proteins and might contribute to the ZIKV-associated neuropathologic sequelae.
... The human dN/dS calculated from a large adult population therefore may be an indicator for selective pressure, which in turn can help prioritize whether a particular gene is more likely to be related to disease. We ranked all X-linked genes by the dN/dS ratio (Supplementary Material, Table S2) and examined the genes with a lowest dN/dS ratio and considered these candidate genes for potential early/severe human phenotypes ( (42)(43)(44)(45). We manually reviewed the remaining functionally uncharacterized genes for potential disease association and found additional candidate genes with clinical relevance. ...
Many new disease genes can be identified through high-throughput sequencing. Yet, variant interpretation for the large amounts
of genomic data remains a challenge given variation of uncertain significance and genes that lack disease annotation. As clinically
significant disease genes may be subject to negative selection, we developed a prediction method that measures paucity of
non-synonymous variation in the human population to infer gene-based pathogenicity. Integrating human exome data of over 6000
individuals from the NHLBI Exome Sequencing Project, we tested the utility of the prediction method based on the ratio of
non-synonymous to synonymous substitution rates (dN/dS) on X-chromosome genes. A low dN/dS ratio characterized genes associated with childhood disease and outcome. Furthermore, we identify new candidates for diseases
with early mortality and demonstrate intragenic localized patterns of variants that suggest pathogenic hotspots. Our results
suggest that intrahuman substitution analysis is a valuable tool to help prioritize novel disease genes in sequence interpretation.
... A number of studies have indicated that the PQBP1 gene is causative for X-linked mental retardation (XLMR) disorders, such as the Renpenning, Sutherland-Haan, Hamel, Porteous and Golabi-Ito-Hall syndromes [10][11][12][13][14][15][16][17][18] . Patients with these diseases frequently share similar symptoms, such as intellectual disability, microcephaly and short stature. ...
... The most common type are frameshift mutations causing a premature termination codon. Such frameshift mutations result in partial or total loss of the C-terminal domain that is functionally important for the interaction between PQBP1 and the spliceosomal U5-15kD [10][11][12][13][15][16][17][18] . Based on these findings, the loss of function of PQBP1 in the pre-mRNA splicing is believed to cause XLMR 12,[19][20][21][22] . ...
... There are seven frameshift mutations in the PQBP1 gene that have been identified in families with XLMR [10][11][12][13][15][16][17][18] . We demonstrate here that all the frameshift mutations reported so far cause the loss of the YxxPxxVL motif that is essential for the U5-15kD binding. ...
A loss-of-function of polyglutamine tract-binding protein 1 (PQBP1) induced by frameshift mutations is believed to cause X-linked mental retardation. However, the mechanism by which structural changes in PQBP1 lead to mental retardation is unknown. Here we present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5-15kD. The U5-15kD hydrophobic groove recognizes a YxxPxxVL motif in PQBP1, and mutations within this motif cause a loss-of-function phenotype of PQBP1 in vitro. The YxxPxxVL motif is absent in all PQBP1 frameshift mutants seen in cases of mental retardation. These results suggest a mechanism by which the loss of the YxxPxxVL motif could lead to the functional defects seen in this type of mental retardation.
