Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V
Department of Internal Medicine II/Cardiology, University of Regensburg, Regensburg, Germany.
Clin Genet. 2003 Oct;64(4):339-49. doi: 10.1034/j.1399-0004.2003.00151.x.
Defects in nine sarcomeric protein genes are known to cause hypertrophic cardiomyopathy (HCM). Mutation types and frequencies in large cohorts of consecutive and unrelated patients have not yet been determined. We, therefore, screened HCM patients for mutations in six sarcomeric genes: myosin-binding protein C3 (MYBPC3), MYH7, cardiac troponin T (TNNT2), alpha-tropomyosin (TPM1), cardiac troponin I (TNNI3), and cardiac troponin C (TNNC1). HCM was diagnosed in 108 consecutive patients by echocardiography (septum >15 mm, septal/posterior wall >1.3 mm), angiography, or based on a state after myectomy. Single-strand conformation polymorphism analysis was used for mutation screening, followed by DNA-sequencing. A total of 34 different mutations were identified in 108 patients: 18 mutations in MYBPC3 in 20 patients [intervening sequence (intron) 7 + 1G > A and Q1233X were found twice], 13 missense mutations in MYH7 in 14 patients (R807H was found twice), and one amino acid change in TPM1, TNNT2, and TNNI3, respectively. No disease-causing mutation was found in TNNC1. Cosegregation with the HCM phenotype could be demonstrated for 13 mutations (eight mutations in MYBPC3 and five mutations in MYH7). Twenty-eight of the 37 mutation carriers (76%) reported a positive family history with at least one affected first-grade relative; only eight mutations occurred sporadically (22%). MYBPC3 was the gene that most frequently caused HCM in our population. Systematic mutation screening in large samples of HCM patients leads to a genetic diagnosis in about 30% of unrelated index patients and in about 57% of patients with a positive family history.
已知9种肌节蛋白基因缺陷可导致肥厚型心肌病（HCM）。连续且无亲缘关系的大量患者队列中的突变类型和频率尚未确定。因此，我们对HCM患者进行了6种肌节基因的突变筛查：肌球蛋白结合蛋白C3（MYBPC3）、肌球蛋白重链7（MYH7）、心肌肌钙蛋白T（TNNT2）、α-原肌球蛋白（TPM1）、心肌肌钙蛋白I（TNNI3）和心肌肌钙蛋白C（TNNC1）。通过超声心动图（室间隔>15mm，室间隔/后壁>1.3mm）、血管造影或根据心肌切除术后的状态，对108例连续患者诊断为HCM。采用单链构象多态性分析进行突变筛查，随后进行DNA测序。在108例患者中总共鉴定出34种不同的突变：20例患者的MYBPC3中有18种突变[内含子7 + 1G > A和Q1233X被发现两次]，14例患者的MYH7中有13种错义突变（R807H被发现两次），以及TPM1、TNNT2和TNNI3中分别有1个氨基酸变化。在TNNC1中未发现致病突变。13种突变（MYBPC3中的8种突变和MYH7中的5种突变）可证明与HCM表型共分离。37名突变携带者中的28名（占76%）报告有阳性家族史，至少有一名一级亲属患病；只有8种突变是散发性的（占22%）。在我们的人群中，MYBPC3是最常导致HCM的基因。对大量HCM患者样本进行系统的突变筛查，在约30%的无亲缘关系的索引患者和约57%有阳性家族史的患者中可得出基因诊断。
