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.
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We thank the families for their participation, generosity and patience, and all of the clinicians who referred study subjects. In particular, we thank the Freeman-Sheldon Parents Support Group for their cooperation; B. Kramer, S. Watkins, H. Escobar and C. Dolcourt for technical assistance; and J. Hall for discussion.
The authors declare no competing financial interests.
Amino acid alignments of the regions surrounding the mutated residues in FSS and SHS patients. (PDF 72 kb)
Electropherograms and restriction digests in FSS and SHS families with respective controls. (PDF 898 kb)
Mutations reported in myosin genes expressed in striated muscles. (PDF 24 kb)
PCR primers and restriction enzymes used for mutation analysis. (PDF 20 kb)
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Toydemir, R., Rutherford, A., Whitby, F. et al. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet 38, 561–565 (2006). https://doi.org/10.1038/ng1775
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