Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Jianshedong Road No. 1, Zhengzhou 450052, China.
Academy of Medical Science, Zhengzhou University, Daxuebei Road No. 40, Zhengzhou 450052, China.
Biomed Res Int. 2021 Mar 4;2021:6624744. doi: 10.1155/2021/6624744. eCollection 2021.
Genetic variants in the gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of variants.
The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure.
A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein.
In this family, we identified a novel variant p.Gly674Trp of as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the gene.
基因中的遗传变异可导致 W olfram 综合征（WS）或常染色体显性非综合征低频听力损失（HL）。本研究旨在探讨一个受影响的中国家系中 HL 的分子基础，以及 变异的基因型-表型相关性。
通过听力学检查和家系分析对五代中国家系的临床表型进行特征描述。对 6 名患者和 4 名正常对照者进行了 129 个已知耳聋基因的靶向外显子组测序和生物信息学分析，以筛选可疑的致病性变异。我们构建了完整的 W FS1 蛋白模型，以评估该变异对蛋白结构的潜在影响。
在 基因中发现了一个新的杂合致病性变异 NM_006005.3 c.2020G>T（p.Gly674Trp），位于 wolframin 蛋白的 C 末端结构域。我们进一步表明，与 HL 相关的 错义变异主要集中在内质网（ER）结构域。相比之下，WS 相关的错义变异随机分布于整个蛋白。
在这个家系中，我们确定了一个新的 变异 p.Gly674Trp 是导致低频感音神经性 HL 的主要致病变异，丰富了 基因的突变谱。
