Mutations in embryonic myosin heavy chain (MYH3) cause Freeman- Sheldon syndrome and Sheldon-Hall syndrome
Mutations in embryonic myosin heavy chain (MYH3) cause Freeman- Sheldon syndrome and Sheldon-Hall syndrome
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DOI：
10.1038/ng1775
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发表时间：
2006-05-01
期刊：
影响因子：
30.8
通讯作者：
Bamshad, MJ
中科院分区：
文献类型：
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作者：
Toydemir, RM;Rutherford, A;Bamshad, MJ
先天性缔约体特征的大多数疾病的遗传基础在很大程度上是未知的。在这里我们表明，胚胎肌球蛋白重链（MYH3）基因中的突变导致Freeman-Sheldon综合征（FSS），是最严重的多个先天性缔约染色（即关节炎）综合症之一，以及所有Sheldon案例的近三分之一 - 霍尔综合征（SHS），是最常见的远端关节炎。 FSS和SHS突变会影响不同的肌球蛋白残基，表明MYH3基因型可以预测表型。结构功能分析表明，几乎所有MYH3突变都被预测会干扰肌球蛋白的催化活性。这些结果增加了越来越多的证据表明，先天性缔约是肌纤维生产中产前缺陷的共同结果。阐明这些综合症的遗传基础重新定义了先天性染色体作为肉体的独特缺陷，并提供了有关迄今为止是一群知名疾病的见解。
The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders.