Functional Evaluation of GJB2 Variants in Nonsyndromic Hearing Loss

Choi, Soo‐Young; Lee, Kyu Yup; Kim, Hyun‐Jin; Kim, Hyo-Kyeong; Chang, Qing; Park, Hong-Joon; Jeon, Chang‐Jin; Lin, Xiaobo; Bok, Jinwoong; Kim, Un-Kyung

doi:10.2119/molmed.2010.00183

Cited by 28 publications

(24 citation statements)

References 88 publications

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“…KID S17F (+*) [ 13 , 40 , 123 , 136 ] (−) (−) S, SNHL. KID TM1 V27I [ 140 ] Normal Normal NS, HL and Normal I33T [ 141 ] (−) n.d. NS, Severe to Profound M34T [ 36 , 115 , 142 – 146 ] (−) (−) NS, Mild to Moderate; S, Profound. PPK V37I, A40G [ 113 , 143 , 147 – 149 ] (−) (−) NS, Mild-Moderate, Severe A40V [ 124 , 136 , 150 , 151 ] Normal (+) S, Profound.…”

Section: Introductionmentioning

confidence: 99%

“…Profound T86R, A88S, L90P [ 132 , 143 , 144 , 147 , 160 , 180 ] (−) (−) NS, Profound, Moderate to Profound, Mild to Moderate A88V [ 136 , 168 , 181 ] n.d. (+) S, Severe to Profound. KID ICL E114G, R127H [ 115 , 140 , 144 , 173 , 178 , 182 , 183 ] (−) (−) NS, Severe to Profound, Profound DelE120 [ 141 , 143 , 147 ] (−) n.d. NS, Severe to Profound TM3 R143Q, R153I [ 133 , 152 , 153 , 183 , 184 ] (−) n.d. NS, Profound R143W [ 133 , 144 , 178 , 185 , 186 ] (−) (−) NS, Profound ECL2 F161S, P173R, D179N, R165W, W172R, R184P, R184Q [ 132 , 141 , 143 , 147 , 152 , 153 , 187 – 190 ] (−) n.d. NS, H...…”

Section: Introductionmentioning

confidence: 99%

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Connexinopathies: a structural and functional glimpse

et al. 2016

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Mutations in human connexin (Cx) genes have been related to diseases, which we termed connexinopathies. Such hereditary disorders include nonsyndromic or syndromic deafness (Cx26, Cx30), Charcot Marie Tooth disease (Cx32), occulodentodigital dysplasia and cardiopathies (Cx43), and cataracts (Cx46, Cx50). Despite the clinical phenotypes of connexinopathies have been well documented, their pathogenic molecular determinants remain elusive. The purpose of this work is to identify common/uncommon patterns in channels function among Cx mutations linked to human diseases. To this end, we compiled and discussed the effect of mutations associated to Cx26, Cx32, Cx43, and Cx50 over gap junction channels and hemichannels, highlighting the function of the structural channel domains in which mutations are located and their possible role affecting oligomerization, gating and perm/ selectivity processes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Connexinopathies: a structural and functional glimpse

et al. 2016

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“… 7 , 8 , 9 , 10 Additional variants V27I and E114G were also evaluated and found to cause hearing loss in certain conditions, including VG homozygotes or a compound heterozygote with VG. 11 Interestingly, defects in hemichannel activities were less severe when both loci were mutated, indicating that V27I compensated for the deleterious effect of E114G. Another interesting case showed that R75Q, a dominant GJB2 mutation, was silenced by the cis recessive mutation c.35delG.…”

Section: Introductionmentioning

confidence: 99%

Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene

Kim

Jung²,

Lee

et al. 2015

Exp Mol Med

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GJB2 alleles containing two cis mutations have been rarely found in non-syndromic hearing loss. Herein, we present a Korean patient with non-syndromic hearing loss caused by the R75Q cis mutation with V37I, which arose de novo in the father and was inherited by the patient. Biochemical coupling and hemichannel permeability assays were performed after molecular cloning and transfection of HEK293T cells. Student's t-tests or analysis of variance followed by Tukey's multiple comparison test was used as statistical analysis. Biochemical coupling was significantly reduced in connexin 26 (Cx26)-R75Q- and Cx26-V37I-transfected cells, with greater extent in Cx26-R75Q and Cx26-R75Q+V37I cells. Interestingly, our patient and his father with the mutations had more residual hearing compared with patients with the dominant mutation alone. Although the difference in hemichannel activity between R75Q alone and R75Q in combination with V37I failed to reach significance, it is of note that there is a possibility that V37I located upstream of R75Q might have the ability to ameliorate R75Q expression. Our study emphasizes the importance of cis mutations with R75Q, as the gene effect of R75Q can be modulated depending on the type of additional mutation.

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“…On the other hand, the other missense variant, p.V291L, in the serine protease domain ( Figure 2 d), was predicted to be non-pathogenic with poor conservation among species, from humans to zebrafish ( Figure 2 c). Additionally, another study from Korea reported that p.V291L was likely to be a rare polymorphism ( Table 2 ) [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

The Analysis of A Frequent TMPRSS3 Allele Containing P.V116M and P.V291L in A Cis Configuration among Deaf Koreans

Kim

Chung

Kim

et al. 2017

IJMS

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We performed targeted re-sequencing to identify the genetic etiology of early-onset postlingual deafness and encountered a frequent TMPRSS3 allele harboring two variants in a cis configuration. We aimed to evaluate the pathogenicity of the allele. Among 88 cochlear implantees with autosomal recessive non-syndromic hearing loss, subjects with GJB2 and SLC26A4 mutations were excluded. Thirty-one probands manifesting early-onset postlingual deafness were sorted. Through targeted re-sequencing, we detected two families with a TMPRSS3 mutant allele containing p.V116M and p.V291L in a cis configuration, p.[p.V116M; p.V291L]. A minor allele frequency was calculated and proteolytic activity was measured. A p.[p.V116M; p.V291L] allele demonstrated a significantly higher frequency compared to normal controls and merited attention due to its high frequency (4.84%, 3/62). The first family showed a novel deleterious splice site variant—c.783-1G>A—in a trans allele, while the other showed homozygosity. The progression to deafness was noted within the first decade, suggesting DFNB10. The proteolytic activity was significantly reduced, confirming the severe pathogenicity. This frequent mutant allele significantly contributes to early-onset postlingual deafness in Koreans. For clinical implication and proper auditory rehabilitation, it is important to pay attention to this allele with a severe pathogenic potential.

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Functional Evaluation of GJB2 Variants in Nonsyndromic Hearing Loss

Cited by 28 publications

References 88 publications

Connexinopathies: a structural and functional glimpse

Connexinopathies: a structural and functional glimpse

Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene

The Analysis of A Frequent TMPRSS3 Allele Containing P.V116M and P.V291L in A Cis Configuration among Deaf Koreans

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