Myosin storage myopathy associated with a heterozygous missense mutation in MYH7

Abstract

Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

Mutations in the β-myosin rod cause myosin storage myopathy via multiple mechanisms

“…Also known as hyaline body myopathy, MSM is a rare, congenital myopathy with variable inheritance that is characterized by the presence of subsarcolemmal accumulations of myosin in the majority of type-I skeletal muscle fibers (8,9). Clinically, patients exhibit variable age of onset ranging from birth through childhood, and occasionally middle age.…”

“…All 4 mutations responsible for MSM, L1793P, R1845W, E1886K, and H1901L, are located in the distal rod region of the protein and have been postulated to result in pathogenesis by perturbing the lateral interactions between coiled-coils ( Fig. 1A) (8)(9)(10).…”

Hyaline Body Myopathy: Adulthood Manifestations

“…Recently two causative genes have been identified in patients with HBM 8,9 . Earlier reports suggest autosomal recessive inheritance, 2 however, autosomal dominant inheritance is strongly favored by the two largest published family pedigrees.…”

“…2 A total of 29 patients have been reported in the literature since then, including an affected family recently published by Bohlega and colleagues. [1][2][3][4][5][6][7][8][9] Variable modes of inheritance including autosomal dominant, autosomal recessive and sporadic patterns have been reported. [2][3][4][5][6][7] Recently, two causative genes, including MYH7 missense mutation and a gene locus at chromosome 3p22.2-p21.32, were identified.…”

“…[2][3][4][5][6][7] Recently, two causative genes, including MYH7 missense mutation and a gene locus at chromosome 3p22.2-p21.32, were identified. 8,9 Hyaline body myopathy has a diverse clinical spectrum, with onset in either childhood or adulthood, varying from mild generalized weakness ABSTRACT: Background: Hyaline body myopathy (HBM) is a rare chronic nonprogressive congenital myopathy, with variable patterns of inheritance. Methods: We describe a patient with congenital HBM with progression of weakness and increasing muscle pain in adulthood.…”