Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy
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DOI：
10.1038/6799
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发表时间：
1999-03-01
期刊：
影响因子：
30.8
通讯作者：
Schwartz, K
中科院分区：
文献类型：
--
作者：
Bonne, G;Di Barletta, MR;Schwartz, K
emry - dreifuss肌营养不良症（EDMD）的特点是早期肘部和跟腱挛缩，缓慢进行性肌肉萎缩和无力，心肌病伴传导阻滞，危及生命(1)。存在两种遗传模式，x连锁（OMIM 310300）和常染色体显性（EDMD-AD; OMIM 181350）。EDMD-AD在临床上与该疾病的x连锁型相同（2-4）。编码emerin的基因EMD的突变是x -连锁形式的原因（5,6）。我们已经将EDMD-AD的位点定位到一个大型法国家系的染色体1q11-q23上的8厘米间隔，并发现其他四个小家系的EMD表型可能与该位点相关。该区域包含层状蛋白A/C基因（LMNA），这是一种候选基因，编码核层状蛋白A和C的两种蛋白，通过选择性剪接产生（7,8）。我们在5个家族中发现了4个与疾病表型共分离的LMNA突变：1个无义突变和3个错义突变。这些结果是第一次鉴定在核层的一个组成部分的突变作为一个遗传性肌肉疾病的原因。与EMD突变一起（参考文献5,6），它们强调了核膜成分在神经肌肉疾病发病机制中的潜在重要性。
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening(1). Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease(2-4). Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form(5,6). We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing(7,8). We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.