Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

Chen, Ying; Hu, Lingxiang; Wang, Xueling; Sun, Changling; Lin, Xin; Li, Lei; Mei, Ling; Huang, Zhiwu; Yang, Tao; Wu, Hao

doi:10.1038/srep33279

Cited by 15 publications

(17 citation statements)

References 29 publications

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“…Functional studies performed in cells and mouse models support this conclusion [40–42]. In consistent with previous reports [6, 12–14], we observed that the HL phenotypes associated with p.V37I varied by onset type, disease site, and degree of HL, implying that other causes, especially environmental factors, influence p.V37I-mediated onset of HL.…”

Section: Discussionsupporting

confidence: 92%

Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis

et al. 2017

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Pathogenic variants in the gap junction protein beta-2 (GJB2) gene are the most common cause of hearing loss. Of these, the p.V37I variant of GJB2 has a high allele frequency (up to 10%) in East Asians. Characterization of the phenotypic spectrum associated with p.V37I, as well as the role of this variant in the onset of hearing loss could have a remarkable effect on future diagnostic strategies. Here, we performed a pedigree analysis of unrelated families exhibiting various hearing phenotypes, and then conducted a meta-analysis to comprehensively assess the association between the p.V37I and the risk of hearing loss. Pedigree analyses showed that both homozygous p.V37I variants, as well as compound heterozygous p.V37I with other GJB2 pathogenic variants, contributed to various phenotypes of hearing loss. Meanwhile, meta-analysis demonstrated that, compared with those in the wild type group, both p.V37I homozygotes and compound heterozygous p.V37I variants were at significantly higher risk of developing hearing loss (odds ratios = 7.14 and 3.63; 95% confidence intervals = 3.01-16.95 and 1.38–9.54, respectively). Conversely, heterozygous p.V37I variants alone did not increase the risk of hearing loss. Given the high allele carriage rate of p.V37I (up to 10%) within the general population, our work not only provides information that might influence future genetic screening policies, but also offers insight into clinical risk evaluation and genetic counseling regarding hearing loss.

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Section: Discussionsupporting

confidence: 92%

Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis

et al. 2017

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“…The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to a broad spectrum of hearing phenotypes from mild-to-moderate hearing loss with reduced penetrance to profound hearing loss. The homozygous p.V37I knockin mice developed progressive, mild-to-moderate hearing loss over the first 4-9 months which modeled the hearing phenotype of the human patients, and confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells [21]. Thus, we regard it as likely pathogenic variants.…”

Section: Variants Classification and Evaluationmentioning

confidence: 84%

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Yuan

et al. 2019

Eur J Hum Genet

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Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

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“…Propidium iodide dye transfer was impaired in GJB2 c.109G>A transfected HEK293T cells 29 . Homozygous knock-in mouse model of c.109G>A in Gjb2 was reported to have progressive mild hearing loss, more pronounced at higher sound frequencies 30 . However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, it was not counted towards strong functional evidence.…”

Section: Functional Evidencementioning

confidence: 99%

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Shen

Oza

Castillo

et al. 2019

Genetics in Medicine

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PURPOSE-Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. METHODS-The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Shen et al.

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Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

Cited by 15 publications

References 29 publications

Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis

Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

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