Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency
Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency
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DOI：
10.1038/sj.ejhg.5201190
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发表时间：
2004-08-01
影响因子：
5.2
通讯作者：
Christiansen, M
中科院分区：
文献类型：
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作者：
Andersen, PS;Havndrup, O;Christiansen, M
编码肌瘤蛋白肌球蛋白结合蛋白C的MYBPC3基因突变是常染色体显性家族性肥厚性心肌病（FHC）最常见的原因之一。我们研究了未选择的81个FHC家族的MYBPC3突变的频率、类型和发病机制，这些家庭连续在三级转诊中心登记。通过单链构象多态性和DNA测序，在10个家族（12.3%）中发现9个突变，其中6个为新突变。外显子2的移码突变清楚地表明单倍不全是FHC的一种发病机制。此外，外显子6和内含子31的剪接位点突变、外显子13的缺失和外显子25的无义突变都会导致密码子过早终止，很可能导致功能丧失和单倍不足。此外，有两个错义突变（D228N和a833t）和一个帧内缺失（DeltaLys813）。我们注意到基于mybpc3的FHC的表型表达在家族内有相当大的变化，我们认为影响mRNA稳定性的突变可能通过部分单倍体不足在疾病的可变外显率和表达性中发挥作用。欧洲人类遗传学杂志（2004）。
Mutations in the MYBPC3 gene, encoding the sarcomere protein myosin-binding protein C, are among the most frequent causes of autosomal dominant familial hypertrophic cardiomyopathy (FHC). We studied the frequency, type, and pathogenetic mechanism of MYBPC3 mutations in an unselected cohort of 81 FHC families, consecutively enrolled at a tertiary referral center. Nine mutations, six of which were novel, were found in 10 (12.3%) of the families using single-strand conformation polymorphism and DNA sequencing. A frameshift mutation in exon 2 clearly suggests that haploinsufficiency is a pathogenetic mechanism in FHC. In addition, splice site mutations in exon 6 and intron 31, a deletion in exon 13, and a nonsense mutation in exon 25, all lead to premature termination codons, most likely causing loss of function and haploinsufficiency. Furthermore, there were two missense mutations (D228N and A833 T) and one in-frame deletion (DeltaLys813). A considerable intrafamilial variation in phenotypic expression of MYBPC3-based FHC was noted, and we suggest that mutations influencing stability of mRNA could play a role in the variable penetrance and expressivity of the disease, perhaps via partial haploinsuffciency. European Journal of Human Genetics (2004).