Author:
Lim Hui Dong,Lee So Min,Yun Ye Jin,Lee Dae Hee,Lee Jun Ho,Oh Seung-Ha,Lee Sang-Yeon
Abstract
AbstractBackgroundWolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome,WFS1heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified twoWFS1heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of theWFS1variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes inWFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.MethodsWe performed molecular genetic test and evaluated clinical phenotypes of threeWFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts ofWFS1variants on stability were predicted by comparing intramolecular interactions. A total of 62WFS1variants associated with DFNA6/14/38 were included in a systematic review.ResultsOne variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val inWFS1is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.ConclusionsWe expanded the genotypic spectrum ofWFS1heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits forWFS1heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
Funder
SNUH Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea
Ministry of Education
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
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