Autosomal dominant myopathy: Missense mutation (Glu-706 → Lys) in the myosin heavy chain IIa gene

Abstract

We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy. The disorder has previously been described in a family with an ''autosomal dominant myopathy, with joint contractures, ophthalmoplegia, and rimmed vacuoles.'' Linkage analysis and radiation hybrid mapping showed that the gene locus (Human Genome Map locus name: IBM3) is situated in a 2-Mb region of chromosome 17p13, where also a cluster of MyHC genes is located. These include the genes encoding embryonic, IIa, IIx͞d, IIb, perinatal, and extraocular MyHCs. Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal. This observation prompted us to investigate the MyHC-IIa gene, since MyHC-IIa is the major isoform in type 2A fibers. The complete genomic sequence for this gene was deduced by using an ''in silico'' strategy. The gene, found to consist of 38 exons, was subjected to a complete mutation scan in patients and controls. We identified a missense mutation, Glu-706 3 Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region. By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family.

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

“…Not all MYH2 missense mutations are recessive as the c.2116G4A (p.(Glu706Lys)) mutation was reported to cause dominant myopathy. 10 The severity of the myopathy was, however, related to the amount of expressed MyHC IIa in muscle, ranging from clinically mild in childhood and a more pronounced and progressive course with increased CK levels in adults. 18 Inactivation of the genes encoding adult fast skeletal myosin heavy chain IIb and IId/x and creation of MyHC IIx and MyHC IIb null mice have indicated that these genes are required for the normal muscle development and function of adult skeletal muscle in the mouse.…”

“…The morphological changes were mainly restricted to type 2A fibers, which were either absent or varied in size and showed structural changes. 8,10,18 A later study of patients of three unrelated families with a recessive myopathy, ophthalmoplegia and the absence of type 2A muscle fibers revealed that all patients were compound heterozygous for truncating mutations in MYH2. 11 More recently it was demonstrated that the affected individuals in a large family with recessive myopathy and ophthalmoplegia linked to chromosome 17 p13.1-p12 were homozygous for a frame shift mutation in MYH2 because of a single-base deletion.…”

“…[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.…”

Clinical, pathological, and genetic mutation analysis of sporadic inclusion body myositis in Japanese people

“…Molecular genetic studies have identified 3 loci for hIBM: IBM1, IBM2, and IBM3 [5,6,7]. Over the past 10 years, there has been an accumulation of evidence suggesting 4 that IBM1, or desmin-related myopathy (DRM; OMIM #601419), is caused by mutations in the Desmin gene on chromosome 2q35 [5].…”

“…The shared genotype and similar phenotypes of DMRV and IBM2 indicates that they are allelic disorders [9,10]. An autosomal dominant type of IBM3 (OMIM #605637), characterized by joint contractures, external ophthalmoplegia, and proximal muscle weakness, results from mutations in the gene encoding myosin heavy chain IIa (MYHC2A or MYH2); this is located on chromosome 17p13.1 [7,11,12]. A recent report that myopathy patients from 3 families carried compound heterozygous mutations in the MYHC2A gene implies that this disorder is inherited via autosomal recessive transmission [12].…”