Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy
Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy
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DOI：
10.1016/j.ajhg.2013.05.004
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
laing, Nigel G.
中科院分区：
文献类型：
--
作者：
Ravenscroft, Gianina;Miyatake, Satoko;laing, Nigel G.
线状肌病（NEM）是一种常见的先天性肌病。在NEM临床谱系的非常严重的一端是遗传上未解决的常染色体隐性胎儿运动障碍序列的病例。我们研究了143个缺乏基因诊断的严重nem影响家庭的跨国队列。我们对6个家族进行了全外显子组测序，并对其他家族进行了靶向基因测序。我们在不同种族的28个明显无关的NEM种中发现了19个KLHL40突变（kelch样家族成员40）。在日本队列中，KLHL40突变占检测个体的28%，被发现是这种严重NEM的最常见原因。受影响个体的临床特征是严重和独特的，包括胎儿运动障碍或运动不足和挛缩、骨折、呼吸衰竭和出生时吞咽困难。分子模型表明错义取代会使蛋白质不稳定。蛋白质研究表明，KLHL40是一种横纹肌特异性蛋白，在KLHL40相关的NEM骨骼肌中缺失。在斑马鱼中，klhl40a和klhl40b的表达主要局限于肌组和骨骼肌，敲低这些同工型会导致肌肉结构的破坏和运动能力的丧失。我们发现KLHL40突变是严重常染色体隐性NEM的常见原因，并表明它在肌肉发育和功能中起关键作用。对于常染色体隐性NEM患者和出现产前症状和/或挛缩的患者以及所有日本重度NEM患者，应优先筛查KLHL40。
Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.