Myosins comprise a large superfamily of adenosine triphosphatases(ATPases)that interact with actin filaments to generate motility or force.Unconventional myosins are implicated in diverse cellular processes including ...Myosins comprise a large superfamily of adenosine triphosphatases(ATPases)that interact with actin filaments to generate motility or force.Unconventional myosins are implicated in diverse cellular processes including organelle trafficking,F-actin organization and cell movement.The unconventional myosin,myosin XVA(MYO15A),is localized at the tips of stereocilia in the inner ear hair cells and plays important roles in the development and maintenance of stereocilia.Mutations in MYO15A/Myo15a genes are responsible for hearing loss DFNB3 and shaker-2 in human and mice,respectively.In the present review,we will discuss the expression and alternative splicing of the MYO15A gene,the biochemical properties of the MYO15A protein and the association of MYO15A mutations with hearing loss.We will also discuss the recent investigations into the mechanism of how MYO15A regulates stereocilia development and maintenance.At present we are just beginning to appreciate the important roles of MYO15A in stereocilia,and further investigations are warranted to fully understand them.展开更多
目的:分析MYO15A基因突变导致的常染色体隐性遗传性耳聋的表型及基因型特点,为基因诊断提供依据,为患者及家庭提供遗传咨询。方法:对上海交通大学医学院附属第九人民医院经二代测序检测诊断为MYO15A基因突变导致耳聋的2例散发病例进行...目的:分析MYO15A基因突变导致的常染色体隐性遗传性耳聋的表型及基因型特点,为基因诊断提供依据,为患者及家庭提供遗传咨询。方法:对上海交通大学医学院附属第九人民医院经二代测序检测诊断为MYO15A基因突变导致耳聋的2例散发病例进行基因的突变分析,并在家系内行Sanger测序验证分析。结合临床资料,依据美国医学遗传学和基因组学会(American College of Medical Genetics and Genomics, ACMG)变异分类指南对突变位点进行致病性判定。结果:2个散发耳聋家系的先证者表型分别为双侧重度听力损失与完全听力损失。鉴定了MYO15A基因4个变异,其中致病变异1个,可能致病变异2个,临床意义未明的剪切位点变异1个。患者Ⅰ携带的c.3524dup(p.Ser1176Valfs*14)变异为已报道致病变异;携带的c.10082+3G>A剪切位点变异,根据ACMG指南判定为临床意义未明。患者双侧佩戴助听器后,右耳平均听阈值37.50 dB,左耳平均听阈值33.75 dB。患者Ⅱ携带c.7441_7442del(p.Leu2481Glufs*86)、c.10250_10252del(p.Ser3417del),根据ACMG指南判定为可能致病的。患者右侧人工耳蜗植入术后8年,听觉行为分级-Ⅱ(categorical auditory performance, CAP-Ⅱ)9分,言语可懂度分级(speech intelligibility rating, SIR)5分。结论:本研究新发现的MYO15A基因罕见的c.7441_7442del突变与剪切位点突变c.10082+3G>A与常染色体隐性遗传性耳聋密切相关,丰富了MYO15A基因突变谱,为遗传性耳聋的遗传咨询提供依据。其次剪切位点致病性评估的应用为相关位点的分类提供参考。展开更多
基金National Key Basic Research Program of China(No.2018YFC1003600)the National Natural Science Foundation of China(No.81771001)+1 种基金Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology(No.SPKLACDB-2019000)the Fundamental Research Funds of Shandong University(No.2018JC025).
文摘Myosins comprise a large superfamily of adenosine triphosphatases(ATPases)that interact with actin filaments to generate motility or force.Unconventional myosins are implicated in diverse cellular processes including organelle trafficking,F-actin organization and cell movement.The unconventional myosin,myosin XVA(MYO15A),is localized at the tips of stereocilia in the inner ear hair cells and plays important roles in the development and maintenance of stereocilia.Mutations in MYO15A/Myo15a genes are responsible for hearing loss DFNB3 and shaker-2 in human and mice,respectively.In the present review,we will discuss the expression and alternative splicing of the MYO15A gene,the biochemical properties of the MYO15A protein and the association of MYO15A mutations with hearing loss.We will also discuss the recent investigations into the mechanism of how MYO15A regulates stereocilia development and maintenance.At present we are just beginning to appreciate the important roles of MYO15A in stereocilia,and further investigations are warranted to fully understand them.
文摘目的:分析MYO15A基因突变导致的常染色体隐性遗传性耳聋的表型及基因型特点,为基因诊断提供依据,为患者及家庭提供遗传咨询。方法:对上海交通大学医学院附属第九人民医院经二代测序检测诊断为MYO15A基因突变导致耳聋的2例散发病例进行基因的突变分析,并在家系内行Sanger测序验证分析。结合临床资料,依据美国医学遗传学和基因组学会(American College of Medical Genetics and Genomics, ACMG)变异分类指南对突变位点进行致病性判定。结果:2个散发耳聋家系的先证者表型分别为双侧重度听力损失与完全听力损失。鉴定了MYO15A基因4个变异,其中致病变异1个,可能致病变异2个,临床意义未明的剪切位点变异1个。患者Ⅰ携带的c.3524dup(p.Ser1176Valfs*14)变异为已报道致病变异;携带的c.10082+3G>A剪切位点变异,根据ACMG指南判定为临床意义未明。患者双侧佩戴助听器后,右耳平均听阈值37.50 dB,左耳平均听阈值33.75 dB。患者Ⅱ携带c.7441_7442del(p.Leu2481Glufs*86)、c.10250_10252del(p.Ser3417del),根据ACMG指南判定为可能致病的。患者右侧人工耳蜗植入术后8年,听觉行为分级-Ⅱ(categorical auditory performance, CAP-Ⅱ)9分,言语可懂度分级(speech intelligibility rating, SIR)5分。结论:本研究新发现的MYO15A基因罕见的c.7441_7442del突变与剪切位点突变c.10082+3G>A与常染色体隐性遗传性耳聋密切相关,丰富了MYO15A基因突变谱,为遗传性耳聋的遗传咨询提供依据。其次剪切位点致病性评估的应用为相关位点的分类提供参考。
