Identification and preliminary functional analysis of two novel congenital cataract associated mutations of Cx46 and Cx50

Yang, Ye; Wu, Menghan; Qiao, Yunfei; Xie, Tingting; Yu, Yinhui; Yao, Ke

doi:10.1080/13816810.2019.1675179

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…Understanding these differences at a mechanistic level are important to developing our understanding of how various connexins have adapted to their unique physiological roles throughout the body, and how aberrancies introduced by mutation lead to disease. Indeed, the NT domains of Cx46 and Cx50 are hotspots of genetic variation associated with congenital cataracts (Beyer et al 2013;Mackay et al 2014;Micheal et al 2018;Zhang et al 2018;Ye et al 2019). A similar integrative approach will be key to providing mechanistic insights into the aetiology of these and other cataract-associated variants and possibly other connexin-linked diseases.…”

Section: Discussionmentioning

confidence: 99%

Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N‐terminal domains

Yue

Haddad

Khan

et al. 2021

The Journal of Physiology

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Gap junctions formed by different connexins are expressed throughout the body and harbour unique channel properties that have not been fully defined mechanistically.r Recent structural studies by cryo-electron microscopy have produced high-resolution models of the related but functionally distinct lens connexins (Cx50 and Cx46) captured in a stable open state, opening the door for structure-function comparison.r Here, we conducted comparative molecular dynamics simulation and electrophysiology studies to dissect the isoform-specific differences in Cx46 and Cx50 intercellular channel function.r We show that key determinants Cx46 and Cx50 gap junction channel open stability and unitary conductance are shaped by structural and dynamic features of their N-terminal domains, in particular the residue at the 9th position and differences in hydrophobic anchoring sites.r The results of this study establish the open state Cx46/50 structural models as archetypes for structure-function studies targeted at elucidating the mechanism of gap junction channels and the molecular basis of disease-causing variants.

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Section: Discussionmentioning

confidence: 99%

Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N‐terminal domains

Yue

Haddad

Khan

et al. 2021

The Journal of Physiology

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“…Three variants were identified in connexin genes GJA8 and GJA3 . A GJA8 p.(Gly22Ser) change, observed in family CRCH137, has been previously reported25 27 28 and is one meiosis short of reclassification as likely pathogenic (table 1, figure 3A). In family CTAS71, the novel p.(Lys131del) change (table 1, figure 3B) is located centrally in the GJA8 protein’s cytoplasmic loop which is a less conserved protein region in general.…”

Section: Resultsmentioning

confidence: 60%

Pathogenic genetic variants identified in Australian families with paediatric cataract

et al. 2022

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ObjectivePaediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort.Methods and analysisSixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing.ResultsDisease-causing variants were confirmed in eight families with variant classification as ‘likely pathogenic’. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP.ConclusionThese findings expand the genotype–phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.

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“…According to the ACMG criteria, these two variants are categorized as likely pathogenic. Previous studies in the literature report that the glycine amino acid located in codon 22 of the GJA3 protein is highly phylogenetically conserved among multiple species, and the change of glycine to serine in the same codon leads to the CC phenotype in these patients [15]. It is also reported in the literature that glutamine located in codon 49 is highly phylogenetically conserved among multiple species.…”

Section: Discussionmentioning

confidence: 88%

Identification of Novel Gene Variants in Turkish Families with Non-Syndromic Congenital Cataracts Using Whole-Exome Sequencing

Türkyılmaz

Kaplan

Yalçın

et al. 2021

Preprint

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Purpose The present study aimed to identify the molecular etiology of non-syndromic congenital cataract (CC) using whole-exome sequencing (WES) analysis. Methods In the present study, ophthalmologic results and pedigree analysis of the families of 12 patients with non-syndromic CC were evaluated. WES analysis was conducted after DNA was isolated from peripheral blood samples obtained from the patients.Results Twelve non-syndromic probands (10 male and 2 female) with bilateral CC were included in the study. Patient age ranged between 1 and 11 months. WES analysis showed pathogenic/likely pathogenic variant in 7 (58%) of the 12 families and variant of unknown significance (VUS) in 5 (42%) of them. All the 13 different variants detected in 9 different CC-related genes were co-segregated with the disease. Autosomal dominant inheritance was found in 7 (58%) of the families and autosomal recessive inheritance was found in 5 (42%) of them.Conclusion To the best of our knowledge, the present research is one of the limited numbers of studies in the Turkish population in which genetically heterogeneous non-syndromic CC was investigated using WES analysis. Novel variants that we identified in DNMP, LSS, and WFS1 genes, which are rarely associated with the CC phenotype, have contributed to the mutation spectrum of this disease. Identifying the relevant molecular genetic etiology allows accurate genetic counseling to be provided to the families.

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Identification and preliminary functional analysis of two novel congenital cataract associated mutations of Cx46 and Cx50

Cited by 9 publications

References 26 publications

Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N‐terminal domains

Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N‐terminal domains

Pathogenic genetic variants identified in Australian families with paediatric cataract

Identification of Novel Gene Variants in Turkish Families with Non-Syndromic Congenital Cataracts Using Whole-Exome Sequencing

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