Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6
Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6
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DOI：
10.1038/ejhg.2013.108
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发表时间：
2014-02-01
影响因子：
5.2
通讯作者：
Kunstmann, Erdmute
中科院分区：
文献类型：
--
作者：
Rost, Simone;Bach, Elisa;Kunstmann, Erdmute
遗传性听力损失是人类最常见的感觉神经性疾病。遗传原因是高度异质性的，迄今为止，在与非综合征性听力损失相关的40多个基因中检测到突变。虽然常染色体隐性和常染色体显性遗传是普遍的，X连锁形式的非综合征性听力障碍是极其罕见的。在这里，我们提出了一个匈牙利三代家庭与X连锁非综合征性先天性听力损失和潜在的遗传缺陷。下一代测序和随后的分离分析检测到所有受影响的家族成员中IV型胶原基因COL4A6的错义突变（c.1771G> A，p.Gly591Ser）。生物信息学分析和表达研究支持这种替代是因果关系。COL4A6编码基底膜IV型胶原的α-6链，其与COL4A5编码的两条α-5链形成异源三聚体。尽管COL4A5突变和涉及COL4A5和COL4A6的连续X染色体缺失与X连锁Alport综合征（一种与耳聋和白内障相关的肾病）相关，但迄今为止，COL4A6单独突变与任何遗传性疾病无关。此外，我们的索引患者和其他受影响的家庭成员显示正常的肾和眼功能，这是不符合Alport综合征，但与非综合征型听力损失。原位杂交和免疫染色表明，在斑马鱼的耳囊和小鼠内耳中的COL4A6同系物的表达，支持其在正常的耳朵发育和功能的作用。总之，我们的研究结果表明COL4A6是与X连锁非综合征性听力损失相关的第四个基因。
Hereditary hearing loss is the most common human sensorineural disorder. Genetic causes are highly heterogeneous, with mutations detected in > 40 genes associated with nonsyndromic hearing loss, to date. Whereas autosomal recessive and autosomal dominant inheritance is prevalent, X-linked forms of nonsyndromic hearing impairment are extremely rare. Here, we present a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss and the underlying genetic defect. Next-generation sequencing and subsequent segregation analysis detected a missense mutation (c.1771G > A, p.Gly591Ser) in the type IV collagen gene COL4A6 in all affected family members. Bioinformatic analysis and expression studies support this substitution as being causative. COL4A6 encodes the alpha-6 chain of type IV collagen of basal membranes, which forms a heterotrimer with two alpha-5 chains encoded by COL4A5. Whereas mutations in COL4A5 and contiguous X-chromosomal deletions involving COL4A5 and COL4A6 are associated with X-linked Alport syndrome, a nephropathy associated with deafness and cataract, mutations in COL4A6 alone have not been related to any hereditary disease so far. Moreover, our index patient and other affected family members show normal renal and ocular function, which is not consistent with Alport syndrome, but with a nonsyndromic type of hearing loss. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. In conclusion, our results suggest COL4A6 as being the fourth gene associated with X-linked nonsyndromic hearing loss.