Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin
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DOI：
10.1086/342380
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发表时间：
2002-09-01
影响因子：
9.8
通讯作者：
Udd, B
中科院分区：
文献类型：
--
作者：
Hackman, P;Vihola, A;Udd, B
胫骨肌营养不良症(TMD)是一种与2q31染色体连锁的常染色体显性遗传性晚发性远端肌病。连接的区域包括编码中央肌瘤蛋白Titin的巨型TTN基因。我们之前已经发现了与TMD相关的继发性Calain-3缺陷，这进一步强调了Titin是候选。我们现在报告了第一个TTN突变导致人类骨骼肌疾病，TMD。在Mex6，TTN的最后一个外显子，一个独特的11个碱基的缺失/插入突变，改变了4个氨基酸残基，与12个无关家系的81名芬兰TMD患者完全共分离。在216个芬兰对照样本中没有发现这种突变。在一个患有TMD的法国家庭中，发现了Mex6基因293,357位的Leu-->；Pro突变。Mex6与已知的M-line titin的calain-3结合位点Mex5相邻。免疫组织化学分析表明，在我们研究的TMD肌肉样本中，针对Titin的M线区域的两个外显子特异性抗体显示了TMD肌肉中特异性的羧基末端Titin表位的缺失，从而暗示M线Titin在TMD疾病表型的发生中存在功能缺陷。
Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.