Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and.
Hum Mol Genet. 2013 Dec 20;22(25):5229-36. doi: 10.1093/hmg/ddt380. Epub 2013 Aug 9.
Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.
先天性肌病是一组以多种特征性组织学异常为特征的遗传性肌肉疾病。我们研究了一个先天性肌病的近亲家庭。全基因组连锁分析和全外显子组测序在受影响个体中发现了 3-羟基酰基辅酶 A 脱水酶 1（HACD1）的纯合无义突变。该突变导致 HACD1mRNA 发生无义介导的衰变，患者肌肉中的 mRNA 水平降至对照组的 31%，并完全消除了 3-羟基酰基辅酶 A 的脱水酶活性，这是超长链脂肪酸（VLCFAs）延长的第三步。我们描述了与以前未知与人类先天性肌病相关的基因中的有害突变相关的临床发现。我们认为 HACD1 基因中的突变导致 VLCFAs 的合成减少，VLCFAs 是膜脂质的成分和生理过程的参与者，导致先天性肌病。这些数据表明 HACD1 对肌肉功能是必要的。
