Watkins H, Rosenzweig A, Hwang D S, Levi T, McKenna W, Seidman C E, Seidman J G
Cardiology Division, Brigham and Women's Hospital, Boston, MA.
N Engl J Med. 1992 Apr 23;326(17):1108-14. doi: 10.1056/NEJM199204233261703.
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.
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.
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.
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.
家族性肥厚型心肌病的特征是心肌肥厚程度各异且症状范围广泛。在三个患病家族中已鉴定出β-心肌肌球蛋白重链基因的不同突变。然而，尚不清楚肌球蛋白突变所致病例的比例以及不同突变对临床结局的影响。
我们使用核糖核酸酶保护分析法，对来自25个无关家族的家族性肥厚型心肌病先证者的β-心肌肌球蛋白重链基因进行筛查；该分析法是检测突变存在及位置的灵敏方法。我们通过分析其核苷酸序列进一步确定突变。对具有各种肌球蛋白突变的家族中该疾病的临床特征进行比较。
在25个家族中的12个家族鉴定出β-心肌肌球蛋白重链基因的7种突变。所有突变均为错义突变（即导致单个氨基酸替换），集中在分子的头部和头杆连接区域。6种突变导致氨基酸电荷改变。氨基酸电荷发生改变的突变患者（如核苷酸403处精氨酸变为谷氨酰胺或核苷酸453处精氨酸变为半胱氨酸）预期寿命明显缩短（平均死亡年龄33岁），而唯一一种未导致电荷改变的突变（Val606Met）患者生存情况近乎正常。然而，不同突变患者在家族性肥厚型心肌病的临床表现上并无明显差异。
在约50%的肥厚型心肌病家族中可鉴定出β-心肌肌球蛋白重链基因的不同错义突变。在这些家族中，可对所有成员做出明确的基因诊断。由于突变位置或其DNA序列改变（或两者）似乎影响生存，我们建议对致病突变的精确界定可为受累成员提供重要的预后信息。
