Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1)

Abstract

The ACTA1 gene encodes skeletal muscle alpha-actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction. ACTA1 disease-causing mutations were first described in 1999, when a total of 15 mutations were known. In this article we describe 177 different disease-causing ACTA1 mutations, including 85 that have not been described before. ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core-like areas. Mixtures of these histopathological phenotypes may be seen in a single biopsy from one patient. Irrespective of the histopathology, the disease is frequently clinically severe, with many patients dying within the first year of life. Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations. To aid molecular diagnosis and establishing genotype-phenotype correlations, we have developed a locus-specific database for ACTA1 variations (http://waimr.uwa.edu.au).

Figure 1

Linear diagram of the ACTA1 gene showing the six coding exons and the location of all mutations. The dominant mutations are in normal text, the recessive mutations are italicised and at the bottom of the list for each exon. The open boxes represent translated regions of each exon, the filled boxes the 5’ and 3’ untranslated regions. See Supp. Table S1 for detailed list of mutations, including the DNA mutation names.

Figure 2

Location of ACTA1 mutations within the actin monomer. The figure was generated with Polyview (http://polyview.cchmc.org/polyview3d.html) based on the Protein Database file 1j6z which does not have locations for the 3 most N-terminal and 3 most C-terminal amino-acids of the mature skeletal muscle α–actin protein. A number of the ACTA1 mutations therefore cannot be placed in the figure, including one of the two core myopathy mutations. A) All mutations colour-coded ribbon diagram. Nemaline myopathy: blue, actin myopathy: cyan, intranuclear rod myopathy: yellow, core myopathy: red, congenital fibre type disproportion: magenta. B) All mutations space fill. C) Recessive nemaline myopathy missense mutations. D) Actin myopathy. E) Intranuclear rod myopathy. F) Congenital fibre type disproportion.

Figure 3

Light and electron microscopic images of the five different histopathologies caused by ACTA1 mutations. A) Light microscopic gomori trichrome stain of nemaline myopathy. B) electron micrograph of nemaline bodies in nemaline myopathy. C) Electron micrograph of an intranuclear rod (arrowed) in intranuclear rod myopathy. D) Electron micrograph of accumulation of actin thin filaments (arrowed) in actin aggregate myopathy. E) Light microscopy of core like areas (NADH staining) in core myopathy. F) Light microscopy (ATP staining pH 10.4) showing small (pale) slow (Type 1) muscle fibres and large (dark) fast (Type 2) muscle fibres in congenital fibre type disproportion. A B, D, E and F courtesy of Caroline Sewry,