Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss

Oh, Se Kyung; Choi, Soo Young; Yu, Song; Lee, Kyu Yup; Hong, Jeong Hee; Hur, Sung Won; Kim, Sang Jeong; Jeon, Chang Jin; Kim, Un Kyung

doi:10.1016/j.bbadis.2012.05.009

Cited by 17 publications

(22 citation statements)

References 34 publications

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“…Our group has postulated that the bilateral nBCNC may have a genetic etiology while the unilateral nBCNC is least likely to have a genetic contribution [12]. However, we were not able to find any candidate variant among the 80 deafness genes in the family SH27 where there was a sibling pair with bilateral nBCNC.…”

Section: Discussioncontrasting

confidence: 68%

Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss

et al. 2013

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Identification of causative genes for hereditary nonsyndromic hearing loss (NSHL) is important to decide treatment modalities and to counsel the patients. Due to the genetic heterogeneity in sensorineural genetic disorders, the high-throughput method can be adapted for the efficient diagnosis. To this end, we designed a new diagnostic pipeline to screen all the reported candidate genes for NSHL. For validation of the diagnostic pipeline, we focused upon familial NSHL cases that are most likely to be genetic, rather than to be infectious or environmental. Among the 32 familial NSHL cases, we were able to make a molecular genetic diagnosis from 12 probands (37.5%) in the first stage by their clinical features, characteristic inheritance pattern and further candidate gene sequencing of GJB2, SLC26A4, POU3F4 or mitochondrial DNA. Next we applied targeted resequencing on 80 NSHL genes in the remaining 20 probands. Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands. These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features. Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private. Despite the advent of whole genome and whole exome sequencing, we propose targeted resequencing and filtering strategy as a screening and diagnostic tool at least for familial NSHL to find mutations based upon its efficacy and cost-effectiveness.

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Section: Discussioncontrasting

confidence: 68%

Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss

et al. 2013

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“…Thus, substitution of the valine with a charged residue is expected to interfere with connexin oligomerization, resulting in a loss of function. The effects of V44E are similar to those of the cataract-associated Cx50 mutation W45S (38), and other connexin point mutations of hydrophobic residues in the TM1/E1 border linked to deafness (26,42). Many of these mutations fail to form functional homotypic or heteromeric gap junction channels and produce dominant inhibition of wild-type conductances.…”

Section: Discussionmentioning

confidence: 81%

Functional effects of Cx50 mutations associated with congenital cataracts

Rubiños

Villone

Mhaske

et al. 2014

American Journal of Physiology-Cell Physiology

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Mutations in connexin50 (Cx50) cause dominant cataracts in both humans and mice. The exact mechanisms by which mutations cause these variable phenotypes are poorly understood. We have examined the functional properties of gap junctions made by three Cx50 mutations, V44E, D47N, and V79L, expressed in mammalian cell lines. V44E trafficked to the plasma membrane properly and formed gap junctional plaques. However, the mutant did not form functional gap junctions when expressed alone, or with wild-type (WT) Cx46 and Cx50, indicating that V44E is a dominant negative inhibitor of WT connexin function. In contrast, D47N subunits did not localize to junctional plaques or form functional homotypic gap junctions; however, mixed expression of D47N and WT subunits of either Cx50 or Cx46 resulted in functional intercellular channels, with high levels of coupling. Single-channel studies indicated that D47N formed heteromeric channels with WT Cx46 with unique properties. Unlike either V44E or D47N, V79L formed functional homotypic intercellular channels. However, the mutation caused an alteration in voltage gating and a dramatic reduction in the single-channel open probability, resulting in much lower levels of conductance in cells expressing V79L alone, or together with WT connexin subunits. Thus, each mutation produced distinct changes in the properties of junctional coupling. V44E failed to form intercellular channels in any configuration, D47N formed only heteromeric channels with WT connexins, and V79L formed homotypic and heteromeric channels with altered properties. These results suggest that unique interactions between mutant and wild-type lens connexins might underlie the development of various cataract phenotypes in humans.

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“…158389; Venlo, Limburg, Netherlands). After GJB2 sequencing, we performed targeted resequencing of the known 129,200 deafness genes (TRS-129 and TRS-200), as previously described [21, 22]. TRS-129 and TRS-200 were performed by Otogenetics (http://www.otogenetics.com/) and SGI (Samsung genomic institute, http://www.samsunghospital.com/dept/main/index.do?DP_CODE=BP7), respectively.…”

Section: Methodsmentioning

confidence: 99%

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

Kim

Lee

et al. 2016

PLoS ONE

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CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

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Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss

Cited by 17 publications

References 34 publications

Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss

Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss

Functional effects of Cx50 mutations associated with congenital cataracts

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

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