Abstract
Skeletal muscle α-actin is the principal protein component of the adult skeletal muscle thin filament. The interaction between skeletal, muscle α-actin and the various myosin heavy chain proteins in the different muscle fibre types generates the force of muscle contraction. Skeletal muscle α-alpha actin is thus of fundamental importance to normal muscle contraction. To date over 140 different disease-causing mutations have been identified in the skeletal muscle α-actin gene ACTA1. These mutations are associated with histologically distinct congenital fibre type including nemaline myopathy, actin myopathy, intranuclear rod myopathy, congenital fibre type disproportion and myopathy with cores. Mutations in ACTA1 are associated with a wide range of clinical severity although the majority of patients tend to have severe congenital-onset disease. Most of the patients have de novo dominant mutations not present in either parent. However mild ACTA1 disease may be dominantly inherited and there are also recessive mutations. The recessive mutations are either genetic or functional null mutations. Patients with no skeletal actin retain cardiac actin, the fetal isoform of actin in skeletal muscle. Information from the clinic suggests that exercise and L-tyrosine may benefit some patients and that in the future decreasing the proportion of mutant actin may ameliorate the disease in some patients.
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References
Vandekerchkhove J, Weber K. At least six different actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. J Mol Biol 1978; 126:783–802.
Zhu M, Yang T, Wei S et al. Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet 2003; 73:1082–1091.
Sheterline P, Clayton J, Sparrow JC. In: Sheterline P, ed. Actin, vol 1. Oxford: Oxford University Press, 1998.
Huxley AF, Niedergerke R. Structural changes during contraction: Interference microscopy of living muscle fibres. Nature 1954; 173:971–973.
Nowak KJ, Wattanasirichaigoon D, Goebel HH et al. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nature Genet 1999; 23:208–212.
Kaindl AM, Ruschendorf F, Krause S et al. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 2004; 41:842–848.
Laing NG, Clarke NF, Dye DE et al. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 2004; 56:689–694.
Agrawal PB, Strickland CD, Midgett C et al. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 2004; 56:86–96.
Wallgren-Pettersson C, Pelin K, Nowak KJ et al. Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord 2004; 14:461–470.
Sparrow JC, Nowak KJ, Durling HJ et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromusc Disord 2003; 13:519–531.
Goebel HH, Anderson JR, Hubner C et al. Congenital myopathy with excess of thin myofilaments. Am J Hum Genet 2001; 68:1333–1343
Ilkovski B, Cooper ST, Nowak K et al. Nemaline Myopathy caused by mutations in the muscle alpha-skeletal-actin gene. Am J Hum Genet 2001; 68:1333–1343.
Ryan MM, Schnell C, Strickland CD et al. Nemaline myopathy: A clinical study of 143 cases. Ann Neurol 2001; 50:312–320.
North KN, Laing NG, Wallgren-Pettersson C et al. Nemaline myopathy: Current concepts. J Med Genet 1997; 34:705–713.
Ilkovski B, Clement S, Sewry C et al. Defining alpha-skeletal and alpha-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy. Neuromuscul Disord 2005; 15:829–835.
D’Amico A, Graziano C, Pacileo G et al. Fatal hypertrophic cardiomyopathy and nemaline myopathy associated with ACTA1 K336E mutation. Neuromuscul Disord 2006; 16:548–552.
Ryan MM, Ilkovski B, Strickland CD et al. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 2003; 60:665–673.
Ilkovski B, Nowak KJ, Domazetovska A et al. Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Hum Mol Genet 2004; 13:1727–1743.
Clarke NF, Ilkovski B, Cooper S et al. The pathogenesis of ACTA1-related congenital fiber type disproportion. Ann Neurol 2007; 61:552–561.
Nowak KJ, Sewry CA, Navarro C et al. Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann Neurol 2007; 61:175–184.
Graziano C, Bertini E, Minetti C et al. Alpha-actin gene mutations and polymorphisms in Italian patients with nemaline myopathy. Int J Mol Med 2004; 13:805–809.
Costa CF, Rommelaere H, Waterschoot D et al. Myopathy mutations in a-skeletal-muscle actin cause a range of molecular defects. J Cell Sci 2004; 117:3367–3377.
Nowak KJ, Laing NG. Sarcomeric protein congenital myopathies—Can successful treatments be developed? In: Bohl J, ed. Neuropathology—Back to the Roots Festschrift for Prof. Dr. Hans Goebel. Aachen: Shaker Verlag, 2002; Pages not numbered consecutively.
Wallefeld W, Krause S, Nowak KJ et al. Severe nemaline myopathy caused by mutations of the stop codon of the skeletal muscle alpha actin gene (ACTA1). Neuromuscul Disord 2006; 16:541–547.
Hutchinson DO, Charlton A, Laing NG et al. Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: Clinical and pathological variability within a kindred. Neuromuscul Disord 2006; 16:113–121.
Marston S, Mirza M, Abdulrazzak H et al. Functional characterisation of a mutant actin (Met132VaI) from a patient with nemaline myopathy. Neuromuscul Disord 2004; 14:167–174.
Bertini E, Porfirio B, Graziano C et al. A mutant actin (Lys336Glu) in a patient with nemaline myopathy and hypertrophic cardiomyopathy. Neuromuscul Disord 2005; 15:693.
Tan P, Briner J, Boltshauser E et al. Homozygosity for a nonsense mutation in the alpha-tropomyosin gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromusc Disord 1999; 9:573–579.
Johnston JJ, Kelley RI, Crawford TO et al. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 2000; 67:814–821.
Schnell C, Kan A, North KN. ‘An artefact gone awry’: Identification of the first case of nemaline myopathy by Dr. RDK Reye. Neuromuscul Disord 2000; 10:307–312.
Corbett MA, Robinson CS, Dunglison GF et al. A mutation in alpha-tropomyosin (slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Molec Genet 2001; 10:317–328.
Joya JE, Kee AJ, Nair-Shalliker V et al. Muscle weakness in a mouse model of nemaline myopathy can be reversed with exercise and reveals a novel myofiber repair mechanism. Hum Mol Genet 2004; 13:2633–2645.
Ryan M, Sy C, Rudge S et al. Dietary L-tyrosine supplementation in nemaline myopathy. J Child Neurol 2007; (in press).
Kalita D. Nonprogressive nemaline myopathy. J Orthomolec Med 1989; 4:70–74.
Crawford K, Flick R, Close L et al. Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period. Mol Cell Biol 2002; 22:5887–5896.
Vandekerckhove J, Bugaisky G, Buckingham M. Simultaneous expression of skeletal muscle and heart actin proteins in various striated muscle tissues and cells. A quantitative determination of the two actin isoforms. J Biol Chem 1986; 261:1838–1843.
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North, K.N., Laing, N.G. (2008). Skeletal Muscle Alpha-Actin Diseases. In: Laing, N.G. (eds) The Sarcomere and Skeletal Muscle Disease. Advances in Experimental Medicine and Biology, vol 642. Springer, New York, NY. https://doi.org/10.1007/978-0-387-84847-1_2
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DOI: https://doi.org/10.1007/978-0-387-84847-1_2
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