Toydemir Reha M, Rutherford Ann, Whitby Frank G, Jorde Lynn B, Carey John C, Bamshad Michael J
Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
Nat Genet. 2006 May;38(5):561-5. doi: 10.1038/ng1775. Epub 2006 Apr 16.
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.
大多数以先天性挛缩为特征的病症的遗传基础在很大程度上尚不清楚。我们在此表明，胚胎肌球蛋白重链（MYH3）基因的突变会导致弗里曼-谢ldon综合征（FSS），这是最严重的多发性先天性挛缩（即关节挛缩症）综合征之一，并且在所有谢ldon-霍尔综合征（SHS）病例中占近三分之一，SHS是最常见的远端关节挛缩症。FSS和SHS突变影响不同的肌球蛋白残基，表明MYH3基因型可预测表型。结构-功能分析表明，几乎所有的MYH3突变预计都会干扰肌球蛋白的催化活性。这些结果进一步证明，先天性挛缩是肌纤维力产生的产前缺陷的共同结果。对这些综合征遗传基础的阐明将先天性挛缩重新定义为肌节的独特缺陷，并为迄今为止了解甚少的一组疾病提供了见解。
