Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment
Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment
复制标题
DOI：
10.1016/j.ajhg.2011.04.012
复制
发表时间：
2011-05-13
影响因子：
9.8
通讯作者：
Kremer, Hannie
中科院分区：
文献类型：
--
作者：
Schraders, Margit;Haas, Stefan A.;Kremer, Hannie
在一个荷兰家庭与X连锁的语言后进行性听力障碍，一个关键的连锁区间被确定为跨越一个区域的12.9 Mb两侧的标记DXS 7108和DXS 7110。该区间与先前描述的DFNX 4基因座重叠，并且包含75个注释基因。随后的下一代测序（NGS）在连锁区间内检测到一种变异，即SMPX中的无义突变。SMPX编码小肌肉蛋白，X连锁（SMPX）。对26名来自未排除X连锁遗传非综合征性听力损伤（NSHI）的小家族的索引患者进行进一步筛查。我们在其中一名患者的SMPX中检测到移码突变。在发现这两种突变的家庭中进行的分离分析显示，这些突变与听力障碍共分离。尽管我们表明SMPX在许多不同的器官（包括人类内耳）中表达，但除了听力障碍之外，患者中没有观察到明显的症状。SMPX先前已被证明在横纹肌中特异性表达，因此似乎不太可能是听力障碍的候选基因。我们假设SMPX在内耳发育和/或IGF-1通路、通过Rac 1的整合素通路或两者中的维持中起作用。
In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both.