Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype

Li, Jinying; Xu, Hongen; Sun, Jianfeng; Tian, Yongan; Liu, Danhua; Qin, Yijing; Liu, Huanfei; Li, Ruijun; Neng, Lingling; Deng, Xiaohua; Xue, Binbin; Yu, Changyun; Tang, Wenxue

doi:10.1155/2021/6624744

Cited by 5 publications

(3 citation statements)

References 52 publications

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“…WFS1 -accociated hearing loss can be caused by in-frame insertions or deletions, multiple protein terminating mutations, missense mutations and so on 25 – 27 . We summarized all types of mutations in the WFS1 gene that have been identified thus far in NSHL from the Human Gene Mutation Database (Tables S1 – S2 ) 28 – 31 . In fact, the most common mutations associated with LFNSHL are missense mutations located in exon 8.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of the WFS1 gene in a Chinese family with autosomal-dominant non-syndrome deafness

Zhao

Zhang

Jiang

et al. 2022

Sci Rep

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To analyse the pathogenic genes and mutations of a family with hereditary deafness. We recruited a three-generation family with NSHL. A detailed medical history inquiry and related examinations were performed. Next-generation sequencing (NGS) was used to confirm the gene mutation in the proband, and Sanger sequencing was used for verification. The effect of the WFS1 mutation on the function and structure of the wolframin protein was predicted by multiple computational software. From the Gene Expression Omnibus (GEO) database, we obtained GSE40585 dataset and performed enrichment analyses. The family clinically manifested as autosomal dominant NSHL. A novel WFS1 c.2421C>G (p.Ser807Arg) mutation was identified in four affected individuals in the pedigree . The p.Ser807Arg mutation is a highly conserved residue and causes an increase in protein stability. It had an important influence on not only amino acid size, charge and hydrophobicity but also protein intermolecular hydrogen bonding and spatial structure. There were differentially expressed genes (DEGs) in GSE40585 dataset. Enrichment analysis revealed that DEGs mainly functioned in amino acid metabolism, signal transduction and dephosphorylation. We reported a novel mutation c.2421C>G (p.Ser807Arg in WFS1. This study expands the mutation spectrum of WFS1.

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Section: Discussionmentioning

confidence: 99%

Mutation analysis of the WFS1 gene in a Chinese family with autosomal-dominant non-syndrome deafness

Zhao

Zhang

Jiang

et al. 2022

Sci Rep

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“…The WFS1 gene encodes “Wolframin”, a transmembrane protein located in the endoplasmic reticulum and ubiquitously expressed [ 191 ]. DFNA6/14/38 was largely described in the United States of America [ 192 , 193 , 194 , 195 , 196 , 197 ], Japan [ 198 , 199 , 200 , 201 , 202 , 203 ], and China [ 133 , 182 , 204 , 205 , 206 , 207 , 208 , 209 , 210 ]. In Europe, DFNA6/14/38 was reported in Dutch [ 191 , 211 , 212 , 213 ], Swiss [ 214 ], Danish [ 215 ], Hungarian [ 216 ], Finnish [ 217 ], and German [ 218 ] families.…”

Section: Autosomal Dominant Non-syndromic Hearing Loss (Dfna)mentioning

confidence: 99%

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

et al. 2023

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Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants.

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“…Depending on its association with other organ abnormalities, the cases of hereditary deafness are generally grouped into two categories, i.e., syndromic HL and nonsyndromic hearing loss (NSHL), accounting for 30% and 70% of the total cases of hereditary deafness, respectively [ 3 ]. The NSHL inheritance patterns include autosomal recessive (80%), autosomal dominant (15-20%), sex chromosome chain disorders (1%), and mitochondrial DNA inheritance (1%) [ 4 ]. To date, a total of 161 genetic loci (68 dominant and 93 recessive) and 134 genes (45 dominant, 74 recessive, and 5 X-linked) have been reported to be associated with NSHL based on the Hereditary Hearing Loss database ( https://hereditaryhearingloss.org/ ; accessed in August 2021).…”

Section: Introductionmentioning

confidence: 99%

A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss

Wang

Zhang

et al. 2022

BioMed Research International

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Background. Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) is an uncommon form of hearing loss (HL) that typically affects frequencies at 2000 Hz and below. Heterozygous variants in the WFS1 gene at the DFNA6/14/38 locus are considered a common cause of LFSNHL. To date, 34 different pathogenic genetic variants have been reported to cause LFSNHL with seven of these variants identified in the Chinese population. However, limited reports are available on the association between WFS1 gene and LFSNHL. Here, we report a five-generation Chinese family with an autosomal dominant inheritance pattern of postlingual and progressive LFSNHL. Methods. Routine clinical and audiological examinations were performed on 16 affected and 7 healthy members in this family. The targeted next-generation sequencing of 127 known deafness genes was performed to identify variants in affected individuals. Sanger sequencing were further employed to confirm the pathogenic variant identified. Results. A novel heterozygous pathogenic genetic variant c.2530G > T (p.Ala844Ser) was identified in the WFS1 gene in all patients of this family. The mutated Ala residue is evolutionarily conserved and cosegregated with HL. The variant was predicted to be deleterious by MutationTaster, PolyPhen-2, LRT, and Fathmm software. Conservation analysis and 3D protein structure model indicated that the variant caused a structural change in the protein. Conclusions. Our present study identifies a novel heterozygous WFS1 variant associated with LFSNHL in a Chinese family.

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Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype

Cited by 5 publications

References 52 publications

Mutation analysis of the WFS1 gene in a Chinese family with autosomal-dominant non-syndrome deafness

Mutation analysis of the WFS1 gene in a Chinese family with autosomal-dominant non-syndrome deafness

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss

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