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.
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。