Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland.
University of Oulu Graduate School, University of Oulu, 90220 Oulu, Finland.
Genes (Basel). 2022 Jun 1;13(6):998. doi: 10.3390/genes13060998.
The objective was to study the genetic etiology of Ménière's disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the gene in family I, one variant in and in family II, and one variant in each of the , , , and genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of and could predispose to MD via the oxidative stress pathway. Identification of and as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.
目的是使用下一代测序技术在三个有三个梅尼埃病（MD）病例的家族中研究 MD 的遗传病因。对芬兰家族的 MD 进行全外显子组测序，以鉴定与 MD 共分离的罕见遗传变异。使用计算和人群数据库估计变异的频率和致病性。使用毛细管测序从其他家族成员中验证和基因分型变体。进行基因 MANIA 分析以研究候选基因的功能途径和蛋白质相互作用。在三个家族中发现了七个与 MD 共分离的罕见变异：一个变异位于 I 家族的 基因中，一个变异位于 II 家族的 基因中，一个变异位于 III 家族的 基因中的每个基因中， 和 。这四个基因与之前的家族性 MD 候选基因具有相同的共表达网络。和 功能障碍可能通过氧化应激途径导致 MD。鉴定为 MD 的候选基因表明，家族性 MD 中的有丝分裂纺锤体形成失调。家族性 MD 的遗传病因是异质的。我们的研究结果表明，在 MD 中，氧化应激和有丝分裂纺锤体形成相关的基因可能起作用，但也强调了 MD 的遗传复杂性。
