SLC26A4基因中新变异c.1185_1196dup (p.(Gly396_Ser399dup))与隐性听力损失相关

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中文摘要

背景： SLC26A4基因（溶质载体家族26成员4）的致病变异是遗传性听力损失的常见原因。SLC26A4基因编码跨膜蛋白pendrin，它是SLC26阴离子转运蛋白家族的成员，主要在内耳、甲状腺和肾脏组织中表达。致病性SLC26A4变异导致非综合征型隐性听力损失（DFNB4）和Pendred综合征（感音神经性听力损失和甲状腺功能障碍）。在许多分析SLC26A4基因的研究中，除了具有两个隐性致病性SLC26A4变异且可做出准确分子遗传学诊断的患者（M2患者）外，还经常发现一组仅有一个致病性SLC26A4变异的患者（M1患者），这造成了诊断问题。M1患者的存在可能反映了常规诊断方法未检测到的SLC26A4基因拷贝数变异（CNVs，缺失/重复）。方法：本研究的目的是使用MLPA（多重连接依赖探针扩增）方法，在十三名属于图瓦共和国（南西伯利亚）原住民的M1患者中寻找SLC26A4基因的缺失/重复，这些患者在遗传性听力损失病因学研究期间仅被鉴定出一个致病性SLC26A4变异。结果：通过MLPA分析和分子克隆，在来自两个相关图瓦家庭的三个M1患者的DNA样本中，发现了一个新变异——SLC26A4基因外显子10中十二个核苷酸的串联重复（c.1185_1196dup）。该变异是一个框内插入，导致在pendrin蛋白的高度保守区域中增加了四个额外氨基酸残基Gly-Phe-Phe-Ser（p.(Gly396_Ser399dup)）。大多数预测程序预测c.1185_1196dup变异对pendrin蛋白的结构和功能具有破坏性影响。c.1185_1196dup变异的致病性得到了以下证据的支持：在发现该变异与致病性SLC26A4变异以复合杂合状态存在的患者家系中，该变异与听力病理共分离，并且该变异在图瓦人对照样本和世界基因组数据库中均不存在。结论：需要功能性体外研究来确认新变异c.1185_1196dup (p.(Gly396_Ser399dup))的潜在有害效应及其与听力病理的关联。

英文摘要

Pathogenic variants in the SLC26A4 gene (solute carrier family 26, member 4) are a common cause of inherited hearing loss. The SLC26A4 gene encodes the transmembrane protein pendrin, a member of the SLC26 anion transporter family, with predominant expression in the inner ear, thyroid, and kidney tissues. Pathogenic SLC26A4 variants cause nonsyndromic recessive hearing loss (DFNB4) and Pendred syndrome (sensorineural hearing loss and thyroid dysfunction). In many studies analyzing the SLC26A4 gene, along with patients who have two recessive pathogenic SLC26A4 variants (M2 patients) and an accurate molecular genetic diagnosis can be made, a group of patients with only one pathogenic SLC26A4 variant (M1 patients) is often identified, which creates a diagnostic problem. The presence of M1 patients may reflect copy number variations (CNVs, deletions/duplications) in the SLC26A4 gene that are not detected by routine diagnostic methods. The aim of the study is to search for deletions/duplications in the SLC26A4 gene using the MLPA (Multiplex Ligation-dependent Probe Amplification) method in thirteen patients belonging to the indigenous people of the Tyva Republic (Southern Siberia), in whom only one pathogenic SLC26A4 variant (M1 patients) was identified during the study of the etiology of hereditary hearing loss. As a result of MLPA analysis and molecular cloning in DNA samples of three M1 patients from two related Tuvinian families, a novel variant was revealed - tandem duplication of twelve nucleotides (c.1185_1196dup) in exon 10 of the SLC26A4 gene. This variant is an in-frame insertion resulting in the inclusion of four additional amino acid residues Gly-Phe-Phe-Ser (p.(Gly396_Ser399dup)) in a highly conserved region of the pendrin protein. Most predictive programs predict the damaging effect of the c.1185_1196dup variant on the structure and function of the pendrin protein. The pathogenicity of the c.1185_1196dup variant is supported by its segregation with hearing pathology in the pedigree of patients in whom it was found in a compound heterozygous state with pathogenic SLC26A4 variants, as well as its absence in a control sample of Tuvinians and in the world genomic databases. Functional in vitro studies are needed to confirm the potentially deleterious effects of the novel c.1185_1196dup (p.(Gly396_Ser399dup)) variant and its association with hearing pathology.