Review
Hereditary myosin myopathies

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Abstract

Hereditary myosin myopathies have emerged as a new group of muscle diseases with highly variable clinical features and onset during fetal development, childhood or adulthood. They are caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. Mutations have been reported in two of the three MyHC isoforms expressed in adult limb skeletal muscle: type I (slow/β-cardiac MyHC; MYH7) and type IIa (MYH2). The majority of more than 200 dominant missense mutations in MYH7 are associated with hypertrophic/dilated cardiomyopathy without signs or symptoms of skeletal myopathy. Several mutations in two different parts of the slow/β-cardiac MyHC rod region are associated with two distinct skeletal myopathies without cardiomyopathy: Laing early onset distal myopathy and myosin storage myopathy (MSM). However, early onset distal myopathy and MSM caused by MYH7 mutations may also occur together with cardiomyopathy. MSM affects proximal or scapuloperoneal muscles whereas Laing distal myopathy primarily affects the dorsiflexor muscles of the toes and ankles. MSM is morphologically characterized by subsarcolemmal accumulation of myosin in type 1 fibers, whereas Laing distal myopathy is associated with variable and unspecific muscle pathology, frequently with hypotrophic type 1 muscle fibers. A myopathy associated with a specific mutation in MYH2 is associated with congenital joint contractures and external ophthalmoplegia. The disease is mild in childhood but may be progressive in adulthood, with proximal muscle weakness affecting ambulation. Mutations in embryonic MyHC (MYH3) and perinatal MyHC (MYH8), which are myosin isoforms expressed during muscle development, are associated with distal arthrogryposis syndromes with no or minor muscle weakness. Clinical findings, muscle morphology and molecular genetics in hereditary myosin myopathies are summarized in this review.

Introduction

Myosin is a molecular motor that converts chemical energy into mechanical force [1]. Conventional, class II myosin is a hexameric protein composed of two myosin heavy chain (MyHC) subunits, each with a molecular weight of approximately 220 kDa, and two pairs of non-identical myosin light chain subunits (essential light chains and regulatory light chains) of approximately 20 kDa molecular weight (Fig. 1). The MyHC has two functional domains: the globular, amino-terminal head domain to which the light chains bind exhibits the motor function and the elongated α-helical coiled-coil carboxy-terminal rod domain has filament-forming properties. Proteolytic enzymes can cleave the MyHC into two sub-fragments: heavy meromyosin (HMM) and light meromyosin (LMM). HMM contains the head region termed sub-fragment 1 (S1) and a portion of the coiled-coil forming sequence referred to as sub-fragment 2 (S2) which connects the myosin head to the thick filament. The globular head, that forms the cross bridges, contains the binding sites for actin and ATP [2]. The S1 motor domain of myosin undergoes conformational changes while bound to the actin filaments, resulting in force production and muscle contraction. It has been suggested that the elongated neck region in S1 acts as a lever arm to amplify small conformational changes in the motor domain into much larger displacements of actin. The LMM is the C-terminal portion of the rod, which lies along the thick filament axis. Accessory proteins, such as α-actinin, myomesin, M-protein, titin, desmin and myosin-binding proteins (MyBP) C and H are necessary for the precise alignment of the thick filaments [3].

Several human conventional class II muscle MyHC genes have been identified [4]. Six skeletal muscle myosin heavy chains are encoded by genes found in a tightly linked cluster on chromosome 17, including MYH1, MYH2, MYH3, MYH4, MYH8, and MYH13[5], [6]. MYH6 and MYH7, which encode cardiac myosin isoforms, are located on chromosome 14. A mutation in MYH6, which encodes the α-cardiac MyHC isoform, is associated with atrial septal defect [7]. MYH11 on chromosome 16 encodes smooth muscle myosin. Mutations in MYH11 are associated with thoracic aortic aneurysm and/or aortic dissection and patent ductus arteriosus [8]. The non-muscle conventional class II myosins IIA and IIB are encoded from MYH9 and MYH10. Mutations in MYH9 are associated with so-called MYH9-related disease [9], characterized by macrothrombocytopenia, granulocyte inclusions, deafness, cataracts and renal failure, and caused by defective myosin assembly [10].

The human muscle MyHC isoforms are presented in Table 1. Three major isoforms are present in adult human limb muscle fibers: MyHC I, also called slow/β-cardiac MyHC, is expressed in slow, type 1 muscle fibers as well as in heart ventricles; MyHC IIa is expressed in fast, type 2A muscle fibers and MyHC IIx is expressed in fast, type 2B muscle fibers [11]. Very rapidly contracting fibers have been found in extraocular muscles that express a specific MyHC isoform: extraocular MyHC [12], [13]. Developing and regenerating muscle fibers express special MyHC isoforms, i.e. embryonic and perinatal MyHC. Two MyHC isoforms are present in the adult human heart; the β-cardiac isoform predominates in the ventricles, whereas the α-cardiac MyHC is the major isoform in the atria [14]. The β-cardiac isoform is identical to MyHC I which is expressed in type 1 muscle fibers. Special MyHC isoforms are found in smooth muscle.

Mutations in MyHC genes causing disease were first described in 1990, in the case of familial hypertrophic cardiomyopathy [15]. A MyHC mutation causing skeletal myopathy was first identified in an autosomal dominant congenital myopathy in 2000 [16]. Several myopathies have now been demonstrated to be associated with MyHC mutations (Table 2); they will be briefly described in this review.

Section snippets

Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles (OMIM #605637)

This myopathy was originally identified as a muscle disorder affecting a large family in western Sweden [17] and is also called “Autosomal dominant myosin heavy chain IIa myopathy (E706K)” [18], and “Hereditary inclusion body myopathy type 3” (IBM3) [19].

Myopathies associated with mutations in MYH3

The distal arthrogryposis (DA) syndromes are a group of disorders characterized by congenital contractures in two or more body areas, with frequent involvement of hands and feet and varying proximal joint involvement [30], [31]. DA may manifest as clenched fists, overlapping fingers, camptodactyly, ulnar deviation and positional foot deformities, often talipes equinovarus. Hypotonia and weakness are not prominent features. DA syndromes frequently show autosomal dominant inheritance but usually

Laing early onset distal myopathy (OMIM #160500)

This form of distal myopathy, with autosomal dominant inheritance, was linked to the MYH7 gene on chromosome 14q11 in 1995, based on a study of an Australian family with 14 affected individuals [41]. Several additional familial and sporadic cases have subsequently been reported from various parts of the world and mutations in MYH7 have been identified in most of these cases.

Clinical features

The trismus-pseudocamptodactyly syndrome (DA7) is associated with congenital inability to open the mouth completely (trismus) with resulting problems in mastication; short finger flexor tendons, resulting in involuntary flexion of the fingers when the wrist is dorsiflected (pseudocamptodactyly), and short leg muscles, resulting in foot deformity [30]. In one kindred with MYH8 mutation there were associated cardiac myxomas and spotty skin pigmentation. These individuals were interpreted as

Conclusions

Considering the abundance (15–25% of total body protein) and importance of myosin for muscle function, mutations that alter structure and function of myosin may eventually be identified in many of the so far molecularly undiagnosed patients with muscle disorders. This is further supported by the fact that numerous mutations in β-cardiac MyHC have now been demonstrated to cause cardiomyopathy and that myosin isoforms are evolutionarily highly conserved [12].

Studies based on the identified

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