Siu B L, Niimura H, Osborne J A, Fatkin D, MacRae C, Solomon S, Benson D W, Seidman J G, Seidman C E
Department of Pediatric Cardiology, Boston Children's Hospital, Boston, MA, USA.
Circulation. 1999 Mar 2;99(8):1022-6. doi: 10.1161/01.cir.99.8.1022.
Inherited gene defects are an important cause of dilated cardiomyopathy. Although the chromosome locations of some defects and 1 disease gene (actin) have been identified, the genetic etiologies of most cases of familial dilated cardiomyopathy remain unknown.
We clinically evaluated 3 generations of a kindred with autosomal dominant transmission of dilated cardiomyopathy. Nine surviving and affected individuals had early-onset disease (ventricular chamber dilation during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers. To identify the causal gene defect, linkage studies were performed. A new dilated cardiomyopathy locus was identified on chromosome 2 between loci GCG and D2S72 (maximum logarithm of odds [LOD] score=4.86 at theta=0). Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, sequences encoding 900 amino acid residues of the cardiac-specific (N2-B) domain were analyzed. Five sequence variants were identified, but none segregated with disease in this family.
A dilated cardiomyopathy locus (designated CMD1G) is located on chromosome 2q31 and causes early-onset congestive heart failure. Although titin remains an intriguing candidate gene for this disorder, a disease-causing mutation is not present in its cardiac-specific N2-B domain.
遗传性基因缺陷是扩张型心肌病的一个重要病因。尽管已经确定了一些缺陷的染色体位置和1个疾病基因（肌动蛋白），但大多数家族性扩张型心肌病病例的遗传病因仍不清楚。
我们对一个具有扩张型心肌病常染色体显性遗传的家族的3代人进行了临床评估。9名存活且患病的个体患有早发性疾病（青少年时期心室腔扩张，30岁左右出现充血性心力衰竭）。该疾病在2名必然携带者中未表现出来。为了确定致病基因缺陷，我们进行了连锁研究。在2号染色体上GCG和D2S72位点之间确定了一个新的扩张型心肌病基因座（在θ=0时最大优势对数[LOD]分数=4.86）。由于编码肌联蛋白（一种细胞骨架肌肉蛋白）的大量基因位于这个疾病区间内，因此对编码心脏特异性（N2-B）结构域900个氨基酸残基的序列进行了分析。确定了5个序列变异，但在这个家族中没有一个与疾病共分离。
一个扩张型心肌病基因座（命名为CMD1G）位于2号染色体q31上，可导致早发性充血性心力衰竭。尽管肌联蛋白仍然是这种疾病的一个有吸引力的候选基因，但其心脏特异性N2-B结构域中不存在致病突变。
