MY015A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation
MY015A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation
复制标题
土耳其听力损失家庭中的 MY015A（DFNB3）突变和新型运动结构域突变的功能建模
DOI：
10.1002/ajmg.a.31937
复制
发表时间：
2007-10-15
影响因子：
2
通讯作者：
Kremer, Hannie
中科院分区：
文献类型：
--
作者：
Kalay, Ersan;Uzumcu, Abdullah;Kremer, Hannie
肌球蛋白XVA是一种非传统的肌球蛋白，与人类常染色体隐性遗传性非综合征性听力损伤（ARNSHI）有关。在Myo 15 A小鼠模型中，前庭功能障碍伴随常染色体隐性听力损失。全基因组纯合性定位和随后的精细定位在两个土耳其家庭与ARNSHI揭示了显着的连锁一个关键区间窝藏一个已知的耳聋基因MYO 15 A染色体17p13.1-17q11.2。MYO 15 A基因的后续测序鉴定出一个新的错义突变c. 5492 G-T（p.Gly1831Val）和一个新的错义突变c. 5492 G-T（p.Gly1831Val）以及一个新的剪接位点突变c.8968 -1G-C。在另外64例无关的ARNSHI指数患者和230例土耳其对照染色体中未检测到这些突变。Gly 1831是位于不同种类肌球蛋白的马达结构域中的保守残基。人肌球蛋白XVa蛋白的马达头域的分子建模表明，Gly 1831 Val突变通过降低骨架的灵活性和减弱信号传递到转换器域所必需的疏水相互作用来抑制动力中风。(C)2007Wiley-Liss，Inc.
Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairement (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harbouring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-T(p.Gly1831Val) and a novel missense mutation, c.5492G-T (p.Gly1831Val) and a novel splice site mutation,c.8968-1G-C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the power-stroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain. (C) 2007Wiley-Liss, Inc.