Niimura H, Bachinski L L, Sangwatanaroj S, Watkins H, Chudley A E, McKenna W, Kristinsson A, Roberts R, Sole M, Maron B J, Seidman J G, Seidman C E
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
N Engl J Med. 1998 Apr 30;338(18):1248-57. doi: 10.1056/NEJM199804303381802.
Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown.
DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed.
Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly.
The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.
心肌肌球蛋白结合蛋白C基因的突变约占家族性肥厚型心肌病病例的15%。这些致病突变的范围以及相关的临床特征尚不清楚。
对无亲缘关系的家族性肥厚型心肌病患者的编码心肌肌球蛋白结合蛋白C的DNA序列进行测定。在16名先证者中发现了突变，这些先证者有574名有遗传这些缺陷风险的家庭成员。确定了这些家庭成员的基因型，并评估了212名心肌肌球蛋白结合蛋白C基因突变家庭成员的临床状况。
在16个家族的先证者中鉴定出12种新突变。4种为错义突变；8种缺陷（插入、缺失和剪接突变）预计会使心肌肌球蛋白结合蛋白C截短。错义突变或截短突变的临床表型与肥厚型心肌病其他遗传病因所观察到的相似，但发病年龄有显著差异。在50岁以下的成年心肌肌球蛋白结合蛋白C基因突变患者中，只有58%（117名患者中的68名）有心肌肥厚；到60岁时疾病外显率仍不完全。总体生存率优于由肌节蛋白基因其他突变引起的肥厚型心肌病患者。这些家族中大多数心脏原因导致的死亡为猝死。
心肌肌球蛋白结合蛋白C基因突变的临床表型通常延迟至中年或老年。心肌肥厚肥厚的延迟出现以及良好的临床病程可能会阻碍对心肌肌球蛋白结合蛋白C基因突变遗传性的认识。对于以肥厚型心肌病为特征的家族成员，成年期进行临床筛查可能是必要的。
