肌联蛋白基因突变与中国人扩张型心肌病

Titin gene mutations in Chinese patients with dilated cardiomyopathy

目的肌联蛋白是由单基因编码的最大蛋白，普遍存在于心肌和骨骼肌，被称为第三肌丝，具有复杂的生物力学性质和生物化学功能。2002年日本研究人员报道了肌联蛋白基因（TTN）第3、14、49号外显子的4个基因突变可能与扩张型心肌病（DCM）发病相关，我国未见相关报道。本研究通过寻找我国DCM患者是否存在TTN的突变，探讨在中国人基因背景下可能存在的TTN的突变及其与我国DCM发病的关系。方法采用聚合酶链反应-单链构象多态性（PCR—SSCP）方法、聚丙烯酰胺凝胶电泳及DNA序列测定等方法对117例DCM患者和120例健康对照者TTN的第3、14、49号外显子的多个位点进行检测、分析。结果在我国DCM患者和健康对照者中未发现与日本DCM患者相同位点的基因突变，而在2例有明显DCM家族史的儿童患者（1．7％）中新发现了位于TTN第49号外显子的13053位点基因突变——G→A突变（G13053A），其导致第4351位点氨基酸由甘氨酸变为天冬氨酸（Gly4351Asp），在健康对照组中未发现此改变。结论本研究首次在中国DCM患者中发现存在于TTN第49号外显子的基因错义突变，该突变可能是DCM重要的病因学机制，尤其可能与早发DCM相关。

Objective Titin is recently known as the largest protein which exists in the stiated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions. Four possible disease-associated mutations located in three exons （3,14,49） of titin gene （TTN） have been identified in Japanese DCM patients in 2002. We observed the possible association of TTN mutation in Chinese patients with DCM. Methods Three exons of TTN （3,14,49） were screened in 117 DCM patients and 120 controls by polymerase chain reaction-single strand conformation polymorphisms （PCR-SSCP） and DNA sequence. SSCP was carried out following a protocol optimized for each PCR fragment after amplification. Abnormal SSCP results were subsequently confirmed by DNA sequencing. Results The mutations reported in Japanese DCM patients were not identified in this patient cohort. A novel mutation [ the G13053A （TFN cDNA sequence, X90568） change resulted in amino acid change at position 4351 （Gly4351Asp）] was found in two young DCM patients from a DCM family （ 1.7% ）. There was no similar mutation in controls. Conclusion This novel Gly4351Asp mutation in TTN might be associated with DCM.