Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1)

Abstract

Mutations in the skeletal muscle alpha-actin gene (ACTA1) associated with congenital myopathy with excess of thin myofilaments, nemaline myopathy and intranuclear rod myopathy were first described in 1999. At that time, only 15 different missense mutations were known in ACTA1. More than 60 mutations have now been identified. This review analyses this larger spectrum of mutations in ACTA1. It investigates the molecular consequences of the mutations found to date, provides a framework for genotype–phenotype correlation and suggests future studies in light of results of investigation of normal and mutant actin in other systems, notably the actin specific to the indirect flight muscles of Drosophila. The larger series confirms that the majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The severity of the disease caused ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood. Overall, the mutations within ACTA1 are randomly distributed throughout the protein. However, the larger series of mutations now available indicates that there may be clustering of mutations associated with some phenotypes, e.g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown.

Introduction

ACTA1 gene mutations have been shown to cause three different congenital myopathies [1].

(i) The first of these is ‘actin myopathy’ (AM), a term first applied by Goebel et al. [2] for a disease phenotype described previously [3], [4] in which patients’ biopsies reveal homogeneous filamentous inclusions containing actin, occupying areas devoid of sarcomeres, which would normally be part of the myofibrillar filament lattice (Fig. 1, Table 1).

(ii) The second is intranuclear rod myopathy (IRM) with characteristic intranuclear inclusions [2], [5] (Fig. 1, Table 1).

(iii) The third, but commonest, disease is nemaline myopathy (NEM) with characteristic sarcoplasmic nemaline bodies (rods) [6], [7] (Fig. 1, Table 1).

More than one phenotype may be caused by one ACTA1 mutation [1] (Table 2, Fig. 2). Further ACTA1 gene mutations are continually being identified in patients with the three conditions. Over 60 ACTA1 mutations are therefore now known (Table 2, Fig. 2). In addition to the nemaline and intranuclear rods and actin accumulations, ACTA1 mutations also effect changes in size and distribution of muscle fibre types.

AM and IRM are rare, but NEM is a more common and better known congenital myopathy [13]. NEM ranges in severity from a paucity of spontaneous movements at birth requiring immediate mechanical ventilation, to mild disease compatible with life to adulthood [14]. The European Neuromuscular Centre (ENMC) International Consortium on Nemaline Myopathy has divided NEM into six different subtypes: severe, intermediate, typical, mild, adult onset and other forms based on the severity of the disease, age of onset and additional features [15] (Table 1). In addition to ACTA1mutations [1], [9], [10], [12], NEM has been associated with mutations in four other genes coding for muscle thin filament proteins. These are: (1) slow α-tropomyosin (TPM3) [16], [17], [18]; (2) nebulin (NEB) [19]; (3) slow troponin T (TNNT1) [20]; and (4) β-tropomyosin (TPM2) [21]. In addition, mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause nemaline bodies as well as central cores in the mixed muscle disorder core–rod myopathy [22], [23]. Linkage analysis indicates that NEB mutations cause the majority of NEM cases. ACTA1 mutations appear to be the second most common cause of NEM [8] at around 20% of cases. The small size of the actin gene makes it easier to find the ACTA1 NEM mutations than those in the giant NEB gene, so more disease-causing mutations are known in ACTA1, with many NEB mutations remaining unidentified.

Mutations in human actin genes, including the cardiac actin gene, ACTC, which produce dilated [24] or hypertrophic [25], [26] cardiomyopathy are a relatively recent discovery. In Drosophila melanogaster, the fruitfly, mutants of the Act88F muscle actin gene, whose expression is largely restricted to flight muscles and which is not therefore required for organism viability, have been known for some time [27], [28]. Mutations in this animal model have clarified the molecular functions of actin and its dysfunction in muscle development and can aid our understanding of human actin mutations.

In this review we will concentrate on 69 characterised ACTA1 gene mutations (Table 2, Fig. 2) with a view to developing an understanding of genotype–phenotype correlations and suggesting future studies. Mutations are distributed through all six coding exons of ACTA1 (Fig. 2). There is as yet no overlap between the mutant ACTA1 residues that produce skeletal myopathies and those in ACTC that cause cardiomyopathies, despite the proteins being 99% identical [29].