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Congenital Contractures and Embryonic Myosin« Back to Volume 22, Issue 3, September 2006 - Table of Contents Congenital contractures can be divided roughly into 2 groups: isolated contractures, such as club foot, and multiple contractures – arthrogryposis, of which several forms can be distinguished clinically. The most common inherited arthrogryposis syndromes affect mainly the distal extremities, ie, the distal arthrogryposis syndromes. Freeman-Sheldon syndrome (FSS; OMIM 193700) is the most severe member of the latter group. In additional to distal contractures, affected infants display distinctive contractures of the orofacial muscles leading to an alternate name – whistling face syndrome. Lesser degrees of orofacial contractures are also found in the Sheldon-Hall syndrome (SHS; OMIM 601680), the most common of the distal arthrogryposis syndromes. Several years ago, Bamshad and colleagues1,2 identified mutations of TNNI2 or TNNT3 in some patients with SHS. These genes encode isoforms of troponin I and troponin T, respectively, which are found in fast-twitch myofibers. These proteins are part of the multimeric troponin-tropomyosin complex of the sarcomere - contractile apparatus of myofibers. No mutations of these genes were found in patients with FSS. However, because of the phenotypic overlap between FSS and SHS, they hypothesized that other elements of the sarcomere could be responsible for FSS. Accordingly, they screened 28 FSS probands, including 7 familial and 21 sporadic cases, for mutations of genes that encode myosin heavy chains, especially genes that are expressed during fetal and/or perinatal development, such as MYH1, MYH3, MYH4 and MYH8. A missense mutation predicted to substitute either a cysteine or a histidine for arginine 672 was detected in 20 or 28 cases. The MYH3 codes for an embryonic myosin heavy chain and Arg672 is highly conserved in all human myosins. Of interest is that a mutation in the paralogous Arg674 in MYH8 was recently found by the authors in a case of another distal arthrogryposis syndrome – trismus-pseudocamptodacytly. Of the 8 cases of FSS not having Arg672 mutations, other mutations of MYH3 were detected in three probands. They also screened 38 independent cases of SHS in whom no mutations of TNNI2 or TNNT3 had been detected. MYH3 mutations were found in 5 of 12 familial and 7 of 26 sporadic cases, although none had the Arg672 mutation characteristic of FSS. Schematic illustration of the contractile complex of muscle. Mutations in genes that encode sarcomeric proteins can cause congenital contractures in either distal arthogryposis syndromes (red) or myopathies (purple). Overall, MYH3 mutations accounted for 38/66 (58%) of FSS and SHS cases. The authors concluded by noting that skeletal muscle function depends on the production of force by sarcomeres, the fundamental unit of contraction in all muscle cells. This force is then propagated to the extracellular matrix by multiple filamentous proteins that couple the sarcomere to the sarcolema. Mutations in proteins involved in force transmission are responsible for muscular dystrophies. Their findings now show that mutations of sarcomeric proteins are frequently responsible for congenital contracture syndromes (Figure). Editor’s CommentThis paper is interesting not only because it explains the genetic basis of many cases of FSS and SHS, but because it provides a clearer conceptual context in which to view congenital contractures and muscular dystrophies. As the authors note, the distal arthrogryposis syndromes are unique myopathies because affected infants show neither weakness nor postnatal muscle damage, implying that other sarcomeric proteins can compensate for defects of embryonic myosin. If so, then it is conceivable that these compensatory mechanisms could be exploited to treat congenital contractures. William A. Horton, MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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