My laboratory has identified muscle diseases associated with mutations in a number of sarcomeric proteins. These include mutation of slow α-tropomyosin in autosomal dominant nemaline myopathy, the first known cause of nemaline myopathy (Laing et al., 1995), mutations in nebulin (Pelin et al., 1999), skeletal muscle α-actin (Nowak et al., 1999), slow-skeletal/β-cardiac myosin (Meredith et al., 2004), cofilin (Agrawal et al., 2007), β-tropomyosin (Lehtokari et al., 2007) and filamin (Duff et al., 2011). Other labs have identified mutations in other sarcomeric proteins. Mutations in sarcomeric proteins cause a large range of diseases, from congenital myopathies resulting in almost complete paralysis at birth, through limb girdle muscular dystrophies, to distal myopathies (Laing & Nowak, 2005). Finding these disease genes has helped families through accurate diagnosis, accurate genetic counselling, prenatal diagnosis and to some extent prognosis. Many unanswered questions remain however. These include how mutations in sarcomeric proteins, fundamental to muscle contraction, expressed in either every muscle fibre in the body (Hackman et al., 2002), or in every muscle in the body (Meredith et al., 2004), cause distal myopathies, muscle diseases which preferentially affect specific muscles in specific patterns and result in characteristic distributions of muscle weakness. Another unanswered question is how to treat these diseases. In our own work we have shown that cardiac α-actin, the fetal α-actin isoform in skeletal muscle, can replace skeletal muscle α-actin in skeletal muscle actin knock-out mice. Skeletal muscle α-actin knockout mice normally die by nine days after birth, mimicking the generally severe phenotype of recessive skeletal muscle actin disease in humans, which is characterized by absence of skeletal muscle actin. Transgenic expression of cardiac actin in skeletal muscle after birth rescued the mice to old age (the longest survivors lived greater than two years) (Nowak et al., 2009). We have thus shown that cardiac actin is a target for therapy for the skeletal muscle actin diseases. These results also raise questions of why during normal development, cardiac actin is expressed in fetal skeletal muscle, but is switched off before birth and replaced with skeletal muscle actin (lkovski et al., 2005), when, from our results, cardiac actin function in skeletal muscle is compatible with normal life span.
Agrawal PB, Greenleaf RS, Tomczak KK, Lehtokari VL, Wallgren-Pettersson C, Wallefeld W, et al. (2007) Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. American Journal of Human Genetics 80(1): 162-7.
Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, et al. (2011) Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. American Journal of Human Genetics 88: 729-40.
Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, et al. (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. American Journal of Human Genetics 71: 492-500.
Ilkovski B, Clement S, Sewry C, North KN, Cooper ST. (2005) Defining α-skeletal and α-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy. Neuromuscular Disordorders; 15: 829-35.
Laing NG, Nowak KJ. (2005) When contractile proteins go bad: the sarcomere and skeletal muscle disease. BioEssays 27(8): 809-22.
Laing NG, Wilton SD, Akkari PA, Dorosz S, Boundy K, et al. (1995) A mutation in the α-tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nature Genetics 9: 75-9.
Lehtokari VL, Ceuterick-de Groote C, de Jonghe P, Marttila M, Laing NG, et al. (2007) Cap disease caused by heterozygous deletion of the β-tropomyosin gene TPM2. Neuromuscular Disorders 17: 433-42.
Meredith C, Herrmann R, Parry C, Liyanage K, Dye DE, Durling HJ, et al. (2004) Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1). American Journal of Human Genetics 75(4): 703-8.
Nowak KJ, Ravenscroft G, Jackaman C, Filipovska A, Davies SM, Lim EM, et al. (2009) Rescue of skeletal muscle α-actin-null mice by cardiac (fetal) α-actin. Journal of Cell Biology 185: 903-15.
Nowak KJ, Wattanasirichaigoon D, Goebel HH, Wilce M, Pelin K, et al. (1999) Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy. Nature Genetics 23(2): 208-12.
Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD, et al. (1999) Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proceedings of the National Academy of Sciences USA 96(5): 2305-10.