Actin mutations are one cause of congenital fibre type disproportion

Centre for Neuromuscular and Neurological Disorders, University of Western Australia.
Annals of Neurology (Impact Factor: 9.98). 11/2004; 56(5):689-94. DOI: 10.1002/ana.20260
Source: PubMed


We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1.

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    • "In general, scoliosis and joint contractures (other than mild Achilles tendon contractures) are relatively uncommon. Mutations associated with CFTD have been found in the TPM3 (MIM# 191030), ACTA1 (MIM# 102610), SEPN1 (MIM# 606210), RYR1 (MIM# 180901), TPM2 (MIM# 190990) and MYH7 (MIM# 160760) genes [2-8]. Despite recent advances, no genetic cause has been found in at least 50% of CFTD patients. "
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    • "Family 1030 produced positive LOD scores at sixteen genomic loci, ten of which approached the theoretical maximum LOD score of 1.329, and which collectively contained over 1,000 candidate genes (Online Resource 3). Both SEPN1 and RYR1 were excluded, as were ACTA1 and TPM3, in which mutations cause congenital fiber type disproportion [18,19], a myopathy clinically similar to MmD. The linkage intervals included the myopathy genes MYOT and CRYAB [1], but neither of these contained coding or splice site mutations by Sanger sequencing. "
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    ABSTRACT: We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that cosegregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T>C (p.C326R) and c.2320T>C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C>T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism.
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