背景：Wolfram综合征1型基因（WFS1），它编码一种跨膜结构蛋白（wolframin），对几个生物过程至关重要，包括适当的内耳功能。不像隐性遗传Wolfram综合征,WFS1杂合变异导致DFNA6/14/38和狼样综合征，以常染色体显性遗传的非综合征性听力损失为特征，视神经萎缩,和糖尿病。这里,我们使用外显子组测序在3个DFNA6/14/38家族中鉴定出2个WFS1杂合变体.我们基于三维（3D）建模和结构分析揭示了WFS1变体的致病性。此外，我们介绍了WFS1相关DFNA6/14/38的人工耳蜗植入(CI)结局,并根据我们的结果和系统评价,提出了基因型-表型相关性.
方法：我们对3个WFS1相关的DFNA6/14/38家族进行了分子遗传学检测和临床表型评价。生成了一个假定的WFS1-NCS1相互作用模型，通过比较分子内相互作用来预测WFS1变体对稳定性的影响。系统评价共纳入62种与DFNA6/14/38相关的WFS1变体。
结果：一种变体是内质网（ER）-腔结构域WFS1（NM_006005.3）中已知的突变热点变体（c.2051C>T：p。Ala684Val),另一个是跨膜结构域6中的新型移码变体（c.1544_1545insA：p。Phe515LeufsTer28）。这两个变种是致病性的，基于ACMG/AMP指南。三维建模和结构分析表明,Ala684的疏水取代(p.Ala684Val）使α螺旋不稳定，并导致WFS1-NCS1相互作用的丧失。此外，p.Phe515LeufsTer28变体截短跨膜结构域7-9和ER-腔结构域，可能损害膜定位和C端信号转导。系统评价显示CI的良好结果。值得注意的是,WFS1中的p.Ala684Val与早发性重度至深度耳聋有关，揭示了一个强大的候选变体forCI。
结论：我们扩展了DFNA6/14/38基础的WFS1杂合变异体的基因型谱，揭示了WFS1突变体的致病性，为WFS1-NCS1相互作用提供了理论依据。我们提出了WFS1杂合变体的一系列表型性状，并证明了有利的功能CI结果，提出p.Ala684Val是CI候选人的一个强有力的潜在标记。
Wolfram 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, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.
We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.
One 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 in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.
We expanded the genotypic spectrum of WFS1 heterozygous 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 for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
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