Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A
Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.
Biochem Biophys Res Commun. 1999 Aug 27;262(2):411-7. doi: 10.1006/bbrc.1999.1221.
Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Molecular genetic analyses have revealed that mutations in 8 different genes cause HCM. Mutations in these disease genes, however, could be found in about half of HCM patients, suggesting that there are other unknown disease gene(s). Because the known disease genes encode sarcomeric proteins expressed in the cardiac muscle, we searched for a disease-associated mutation in the titin gene in 82 HCM patients who had no mutation in the known disease genes. A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient. This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actitin in the yeast two-hybrid assay. These observations suggest that the titin mutation may cause HCM in this patient via altered affinity to alpha-actinin.
肥厚型心肌病（HCM）的特征是心室肥厚并伴有肌原纤维排列紊乱。分子遗传学分析表明，8种不同基因的突变可导致HCM。然而，这些疾病基因的突变仅在约一半的HCM患者中被发现，这表明存在其他未知的疾病基因。由于已知的疾病基因编码在心肌中表达的肌节蛋白，我们在82例已知疾病基因无突变的HCM患者中寻找肌联蛋白基因中的疾病相关突变。在一名患者中发现了密码子740处的G到T颠换，即从CGC变为CTC，导致精氨酸被亮氨酸取代。在500多条正常染色体中未发现该突变，并且在酵母双杂交试验中该突变增加了肌联蛋白与α-辅肌动蛋白的结合亲和力。这些观察结果表明，肌联蛋白突变可能通过改变对α-辅肌动蛋白的亲和力而导致该患者发生HCM。
