Department of Medicine, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.
Center for Statistical Genetics, Sergievsky Center and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Genes (Basel). 2021 Nov 6;12(11):1765. doi: 10.3390/genes12111765.
Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target . The data demonstrates that the identified mutation compromises the function of and support its implication in HI. This study is the second report, worldwide, to implicate in HI and suggests that it should be included in diagnostic HI panels.
听力障碍（HI）是一种感觉障碍，在南非的活产儿中患病率为 0.0055。对一个南非家族中表现出进行性、常染色体显性非综合征 HI 的 DNA 样本进行了全外显子组测序，发现了一个新的单等位基因变异[c.1244GC;p.(C415S)]，被认为是潜在的致病变异。通过 Sanger 测序证实了该变异的共分离。该变异不存在于数据库、103 名健康南非对照者和 52 名孤立 HI 的南非先证者中。计算机分析表明， 中的 p.C415S 变异取代了一个保守的半胱氨酸，导致周围二级结构和二硫键发生变化，最终导致 REST 的三级结构改变。使用在 HEK-293 细胞中外源表达的 GFP 标记的野生型（WT）和突变型 的定位研究表明，WT REST 仅定位于细胞核；然而，突变蛋白在整个细胞中定位。此外，突变型 REST 抑制其已知靶标的能力受损。数据表明，鉴定出的突变削弱了 的功能，并支持其在 HI 中的作用。本研究是全球范围内第二项表明 参与 HI 的研究，并建议将其纳入 HI 的诊断面板。
