Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations

Abstract

Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. It is a major determinant of the physiological properties of each of the three muscle fibre types that make up the skeletal muscles. Heterozygous dominant missense mutations in myosin heavy chain genes cause various types of cardiomyopathy and skeletal myopathy, but the effects of myosin heavy chain null mutations in humans have not previously been reported. We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2. Five adult patients, two males and three females, from three unrelated families in UK and Finland were clinically assessed and muscle biopsy was performed in one patient from each family. MYH2 was sequenced and the expression of the corresponding transcripts and protein was analysed in muscle tissue. The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis. Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue. No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced. All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations. Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function. The relatively mild phenotype is interesting in relation to the more severe phenotypes generally seen in relation to recessive null mutations in sarcomeric proteins.

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

“…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. 20 In this study, MYH2 was considered as the plausible disease-causing gene because of the clinical findings of ophthalmoplegia in addition to muscle biopsy findings of absence or abnormal type 2A muscle fibers.…”

“…The first primer pair spans exon 1 to 10 as previously described 11 and the second primer pair was 5 0 -GGAGGAAAAGTGA CGGTGAA-3 0 (forward primer, corresponding to nucleotide 169-188 of human MyHC IIa cDNA sequence; GenBank accession number: AF111784.1, GI: 4808812) combined with 5 0 -ATCTGTGGCCATCAGTTCTTCCT-3 0 (backward primer, corresponding to nucleotide 986-1008 of human MyHC IIa cDNA). The resulting PCR products were analyzed by sequencing.…”

“…11 To analyze the relative expression of different MyHC isoforms in muscle tissue at the transcript level, fragment analysis of multiplex PCR of cDNA using MyHC-specific primers was performed as previously described. 18 …”

“…This variant was previously identified in two patients from Finland. 11 The unaffected mother had only the c.2405T4A mutation (p.Leu802Ter) and the unaffected brother was heterozygous for the c.1331C4T mutation (p.Arg445Cys) indicating that the c.1331C4T mutation was inherited from the father, who was not available for investigation. Sequence analysis of cDNA in the region covering exon 15 through exon 20 of MYH2 demonstrated homozygosity for the wild-type c.…”

“…[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.…”