CHARACTERISTICS AND PROGNOSTIC IMPLICATIONS OF MYOSIN MISSENSE MUTATIONS IN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY
CHARACTERISTICS AND PROGNOSTIC IMPLICATIONS OF MYOSIN MISSENSE MUTATIONS IN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY
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DOI：
10.1056/nejm199204233261703
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发表时间：
1992-04-23
影响因子：
158.5
通讯作者：
SEIDMAN, JG
中科院分区：
文献类型：
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作者：
WATKINS, H;ROSENZWEIG, A;SEIDMAN, JG
背景 家族性肥厚型心肌病的特点是不同程度的心肌肥厚和广泛的症状。在三个受影响的家族中已经确定了β-心肌肌球蛋白重链基因的不同突变。然而，无论是可归因于肌球蛋白突变的病例比例还是不同突变对临床结果的影响都是未知的。 使用核糖核酸酶保护试验，我们筛选了25个家族性肥厚型心肌病无关家族的先证者的β-心肌肌球蛋白重链基因，该试验是检测突变的存在和位置的敏感方法。我们通过分析它们的核苷酸序列进一步确定了突变。比较不同肌球蛋白突变家系的临床特征。 在25个家族中的12个家族中发现了7个β-心肌肌球蛋白重链基因突变。所有这些都是错义突变（即，引起单个氨基酸的取代）聚集在分子的头部和头部-杆连接区。六个突变导致氨基酸电荷的变化。具有改变改变氨基酸电荷的突变（例如在核苷酸403处从精氨酸变为谷氨酰胺或在核苷酸453处从精氨酸变为半胱氨酸）的患者具有显著较短的预期寿命（死亡时的平均年龄为33岁），而具有一个未产生电荷变化的突变（Val606Met）的患者几乎具有正常的生存期。然而，不同突变的患者在家族性肥厚性心肌病的临床表现上没有明显差异。 在大约50%的肥厚型心肌病家族中可以发现β-心肌肌球蛋白重链基因的不同错义突变。在这些家庭中，可以在所有成员中进行明确的遗传诊断。由于突变或其DNA序列改变（或两者）的位置似乎影响生存，我们建议，致病突变的精确定义可以提供重要的预后信息受影响的成员。
Background. Familial hypertrophic cardiomyopathy is characterized by a variable degree of myocardial hypertrophy and a wide range of symptoms. Different mutations in the beta-cardiac myosin heavy-chain gene have been identified in three affected families. However, neither the proportion of cases attributable to myosin mutations nor the effects of different mutations on clinical outcome are known.Methods. Using a ribonuclease protection assay, we screened the beta-cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy; this assay is a sensitive method for detecting the presence and location of mutations. We further defined the mutations by analyzing their nucleotide sequences. The clinical features of the disease were compared in families with various myosin mutations.Results. Seven mutations in the beta-cardiac myosin heavy-chain gene were identified in 12 of the 25 families. All were missense mutations (i.e., causing the substitution of a single amino acid) clustered in the head and head-rod junction regions of the molecule. Six mutations resulted in a change in the charge of the amino acid. Patients with mutations that changed the charge of the altered amino acid (such as that from arginine to glutamine at nucleotide 403 or from arginine to cysteine at nucleotide 453) had a significantly shorter life expectancy (mean age at death, 33 years), whereas patients with the one mutation that did not produce a change in charge (Val606Met) had nearly normal survival. However, patients with different mutations did not differ appreciably in their clinical manifestations of familial hypertrophic cardiomyopathy.Conclusions. Different missense mutations in the beta-cardiac myosin heavy-chain gene can be identified in approximately 50 percent of families with hypertrophic cardiomyopathy. In those families, a definite genetic diagnosis can be made in all members. Since the location of a mutation or its DNA-sequence alteration (or both) appears to influence survival, we suggest that the precise definition of the disease-causing mutation can provide important prognostic information about affected members.