Hofrichter Michaela A H, Mojarad Majid, Doll Julia, Grimm Clemens, Eslahi Atiye, Hosseini Neda Sadat, Rajati Mohsen, Müller Tobias, Dittrich Marcus, Maroofian Reza, Haaf Thomas, Vona Barbara
Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
BMC Med Genet. 2018 May 18;19(1):81. doi: 10.1186/s12881-018-0598-5.
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
基因异质性和近亲结婚使伊朗的隐性遗传性听力损失成为第二常见的遗传疾病。先前在两个巴基斯坦家庭中，仅在S1PR2基因中报道的两个致病变异（c.323G>C，p.Arg108Pro和c.419A>G，p.Tyr140Cys）与常染色体隐性听力损失（DFNB68）相关。我们描述了在一个来自伊朗近亲五代家庭的四名受影响个体中鉴定出的S1PR2基因中一个新的纯合c.323G>A，p.Arg108Gln致病变异。
对一个来自伊朗五代家庭的受影响个体进行了116个听力损失相关基因的全外显子组测序和生物信息学分析。对p.Arg108交换进行了分离分析和三维蛋白质建模。
先前鉴定出带有S1PR2致病变异的两个巴基斯坦家庭表现出严重听力损失，本研究中描述的受影响伊朗个体中也观察到了这种情况。有趣的是，我们在一名受影响个体中确认了混合性听力损失。三维蛋白质建模表明，p.Arg108位置在配体受体相互作用中起关键作用，而p.Arg108Gln变化会干扰这种相互作用。
总之，我们报告了S1PR2基因的第三个总体突变，也是巴基斯坦人群以外的首次报告。此外，我们描述了一个新的变异，它在与先前报道的一个巴基斯坦家庭（p.Arg108Pro）相同的氨基酸残基中导致了氨基酸交换（p.Arg108Gln）。这一发现强调了p.Arg108氨基酸在正常听力中的重要性，并证实和巩固了S1PR2在常染色体隐性听力损失中的作用。
