Embryonic Myosin Heavy-Chain Mutations Cause Distal Arthrogryposis and Developmental Myosin Myopathy That Persists Postnatally

Abstract

Background: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied.Objectives: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations.Design: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

“…16,17 Similarly, the c.769C4T (p.(Ala234Thr)) mutation in MYH3, which is paralogous to the MYH2 p.(Ala236Thr) mutation found in patient B1, was demonstrated to cause Sheldon-Hall syndrome with dominant inheritance in a three-generation family. 16 The p.Met531Thr mutation, which was identified in patient C, may impair contractile function as Met531 is located at the surface of the actin-binding site within a highly conserved a-helical structure. 21 In slow/b cardiac MyHC (MYH7), a missense mutation c.1680T4C (p.(Ser532Pro)) in this a-helical structure is associated with dilated cardiomyopathy with dominant inheritance.…”

“…The paralogs of the p.Thr178Ile and p.(Ala236Thr) mutations are dominant in embryonic MyHC (MYH3) where they cause distal arthrogryposis syndromes. 16,17 One plausible explanation would be that embryonic MyHC is the predominant MyHC isoform during early development, which may cause high vulnerability to heterozygous mutations. Similarly, a missense mutation at residue p.Arg442 in slow/b cardiac, paralogous to MYH2 p.Arg445, is dominant.…”

“…[5][6][7] These include autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles (OMIM #605637), which was first reported as inclusion body myopathy (IBM3), caused by a single point mutation in the fast IIa MyHC gene (MYH2); [8][9][10] recessive myopathy with ophthalmoplegia because of truncating MYH2 mutations; 11 Laing early-onset distal myopathy (OMIM #160500) 12,13 and myosin storage myopathy (OMIM #608358), 14 caused by different mutations in the slow/ b-cardiac MyHC gene (MYH7); Trismus-pseudocamptodactyly syndrome (OMIM #158300), caused by mutation in fetal MyHC (MYH8); 15 distal arthrogryposis (DA) type 1 (OMIM #108120), type 2A (OMIM # 193700; Freeman-Sheldon syndrome) and type 2B (OMIM # 601680; Sheldon-Hall syndrome), caused by mutations in embryonic MyHC (MYH3). 16,17 Here we describe for the first time the clinical findings, muscle morphology and molecular genetic characteristics in six patients from four unrelated families with recessive missense mutations in MYH2 and also a patient with a novel recessive truncating MYH2 mutation. The results support the concept that recessive missense mutations and truncating mutations as well as dominant missense mutations in MYH2 may cause myopathy with ophthalmoplegia as an important clinical finding.…”

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

“…Immunohistochemical staining of embryonic and fetal myosin heavy chains (DSHB F1.652 and Leica NCL MHCn) was performed as previously described. 8 For immunofluorescence microscopy, cryostat sections were fixed, stained and mounted mainly as described. 9 Antibodies used in this study are (1) mouse IgG1 monoclonal antibody XR1 against Xin isoforms A and B, 10 dilution 1:10; (2) anti-filamin C mouse IgA monoclonal antibody RR90, 11 dilution 1:10; and (3) rabbit polyclonal antiserum specific for desmin, dilution 1:100 (Cat.…”

Arthrogryposis: A Review and Update

“…Arthrogryposis also occurs in infants with inherited mutations in genes that encode skeletal muscle acetylcholine receptor proteins, or proteins associated with these receptors (e.g., rapsyn [RAPSN]) [53][54][55] . Congenital myopathies that are sometimes associated with arthrogryposis can be caused by mutations of genes that encode fetal skeletal-muscle myosin heavy chains 32,56 , skeletal-muscle thin filament proteins 57,58 , and the ryanodine receptor protein [59][60][61] . Congenital myotonic dystrophy causes arthrogryposis 62 because of the toxicity of RNA encoded by a triplet repeat expansion in the 3-prime untranslated region of the dystrophia myotonica protein kinase (DMPK) gene 63 .…”