A Multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy
A Multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy
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DOI：
10.1002/humu.20708
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发表时间：
2008-06-01
期刊：
影响因子：
3.9
通讯作者：
del Castillo, Ignacio
中科院分区：
文献类型：
--
作者：
Rodriguez-Ballesteros, Montserrat;Reynoso, Raul;del Castillo, Ignacio
常染色体隐性遗传性非综合征性听力损伤（NSHI）是一种异质性疾病，迄今已报道了53个遗传位点，29个基因已被鉴定。其中之一，OTOF，编码otoferlin，一种膜锚定的钙结合蛋白，在听觉内毛细胞带状突触的突触囊泡的胞吐中起作用。我们已经调查了耳聋的患病率和范围，导致OTOF基因突变。708名西班牙人、83名哥伦比亚人和30名阿根廷人的常染色体隐性遗传性NSHI无关受试者队列中筛选常见的p.Gln829X突变。在复合杂合子中，通过DNA测序鉴定第二个突变等位基因。总共有23名西班牙人、2名哥伦比亚人和2名阿根廷人被证明携带两种OTOF突变等位基因。其中，1名哥伦比亚和13名西班牙受试者出现听神经病。此外，来自几个国家的诊断为听神经病的20名无关受试者的队列通过DNA测序筛选OTOF突变。这些受试者中共有11人显示携带OTOE的两个突变等位基因。总共鉴定了OTOF基因的18个致病性和4个中性新等位基因。单倍型分析标记接近OTOF表明一个共同的创始人为新的c.2905_2923 delins CTCCGAGCGCA突变，经常发现在阿根廷。我们的研究结果证实，OTOF基因突变与一个表型的语前，深刻的NSHI，并表明，OTOF突变是遗传性听神经病的主要原因。
Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness, causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOE In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923 delins CTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.