Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Am J Hum Genet. 2013 Jul 11;93(1):6-18. doi: 10.1016/j.ajhg.2013.05.004. Epub 2013 Jun 6.
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.
先天性肌病中的杆状体肌病（Nemaline myopathy，NEM）较为常见。在 NEM 临床谱的非常严重端，存在遗传上无法解决的常染色体隐性胎儿运动不能序列病例。我们研究了一个缺乏基因诊断的 143 个严重 NEM 受累家庭的多国队列。我们对 6 个家系进行了全外显子组测序，对其他家系进行了靶向基因测序。我们在来自不同种族的 28 个明显无关的 NEM 家族中发现了 KLHL40（kelch-like family member 40）中的 19 个突变。在日本队列中，KLHL40 突变占受检个体的 28%，是这种严重形式的 NEM 的最常见原因。受影响个体的临床特征严重且独特，包括胎儿运动不能或运动减少以及出生时的挛缩、骨折、呼吸衰竭和吞咽困难。分子建模表明，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 骨骼肌中不存在。在斑马鱼中，klhl40a 和 klhl40b 的表达主要局限于肌节和骨骼肌，这些亚型的敲低导致肌肉结构破坏和运动丧失。我们鉴定出 KLHL40 突变是常染色体隐性严重 NEM 的常见原因，并表明其在肌肉发育和功能中起关键作用。在具有产前症状和/或挛缩的常染色体隐性 NEM 受累个体以及所有日本严重 NEM 个体中，KLHL40 的筛查应优先进行。
