Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss

Nonsyndromic Hereditary Hearing Loss is a common disorder accounting for at least 60% of prelingual deafness. GJB2 gene mutations, GJB6 deletion, and the A1555G mitochondrial mutation play a major role worldwide in causing deafness, but there is a high degree of genetic heterogeneity and many genes involved in deafness have not yet been identified. Therefore, there remains a need to search for new causative mutations. In this study, a combined strategy using both linkage analysis and sequencing identified a new mutation causing hearing loss. Linkage analysis identified a region of 40 Mb on chromosome 5q13 (LOD score 3.8) for which exome sequencing data revealed a mutation (c.7873 T>G leading to p.*2625Gluext*11) in the BDP1 gene (B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB) in patients from a consanguineous Qatari family of second degree, showing bilateral, post-lingual, sensorineural moderate to severe hearing impairment. The mutation disrupts the termination codon of the transcript resulting in an elongation of 11 residues of the BDP1 protein. This elongation does not contain any known motif and is not conserved across species. Immunohistochemistry studies carried out in the mouse inner ear showed Bdp1 expression within the endothelial cells in the stria vascularis, as well as in mesenchyme-derived cells surrounding the cochlear duct. The identification of the BDP1 mutation increases our knowledge of the molecular bases of Nonsyndromic Hereditary Hearing Loss and provides new opportunities for the diagnosis and treatment of this disease in the Qatari population.非综合征性遗传性听力损失（Nonsyndromic Hereditary Hearing Loss）是一种常见的遗传性感官疾病，至少占语前聋总病例的60%。GJB2基因突变、GJB6基因缺失以及A1555G线粒体突变是全球范围内引发耳聋的主要致病因素，但耳聋的遗传异质性极高，尚有众多与耳聋相关的致病基因尚未被明确鉴定。因此，学界仍需开展新的致聋突变探索工作。本研究采用连锁分析（linkage analysis）与测序相结合的联合策略，成功鉴定出一种全新的致听力损失突变。连锁分析在5号染色体q13区域定位到一段40 Mb的连锁区间（对数优势比得分（LOD score）为3.8）；对外显子组测序（exome sequencing）数据的分析显示，在一个二级亲缘的卡塔尔近亲婚配家系的患者中，BDP1基因（即RNA聚合酶III转录起始因子IIIB亚基B双prime 1）存在一处突变（c.7873 T>G，可导致蛋白变异p.*2625Gluext*11），该家系患者表现为双侧、语后起病的中重度感音神经性听力损失。该突变破坏了转录本的终止密码子，致使BDP1蛋白延长11个氨基酸残基。此延伸序列未包含任何已知的结构基序，且在各物种间无序列保守性。对小鼠内耳开展的免疫组织化学（immunohistochemistry）研究显示，Bdp1蛋白在血管纹内皮细胞以及耳蜗管周围的间充质来源细胞中均有表达。本次BDP1致病变异的发现，加深了我们对非综合征性遗传性听力损失分子致病基础的认知，也为卡塔尔人群中该疾病的临床诊断与治疗提供了新的契机。