New findings that shed light on how genetic damage to muscle cell proteins can lead to the development of the rare muscle-wasting disease, nemaline myopathy, are reported today (15 March) in the Biochemical Journal.
Professor Laura Machesky and colleagues from the CRUK Beatson Institute for Cancer Research in Glasgow, tested cultures of muscle cells that displayed mutations of the ACTA1 gene to determine how the mutations affected the biochemical pathways leading to the muscle damage seen in nemaline myopathy.
The ACTA1 gene controls the production of actin, one of the main structural proteins in muscle; mutations in this gene cause 15-20% of cases of nemaline myopathy, an inherited muscle wasting disease similar to muscular dystrophy. Around 140 different mutations of the ACTA1 gene can occur; around a third of these have been biochemically characterized to determine how they affect actin. The mutations cause a wide variety of defects in the biochemical behaviour of actin, but all cause defects in the structure of muscle cells leading to cell and tissue damage and wasting. The researchers discovered that not only do disease-causing mutations in actin lead to weakening of the cell's internal support system, but they also cause changes in the genetic control of other biochemical pathways such as the serum-response factor pathway (SRF). When actin binds to a protein called MAL (originally named megakaryoblastic leukaemia-1) in the cell's nucleus, it switches on the SRF pathway. Actin damaged by mutations doesn't bind properly and the SRF pathway isn't fully activated.
The SRF signalling pathway has a role in muscle development and maintenance. The presence of myopathy-causing mutant actin protein leads to alteration in the pathway that could promote muscle cell degeneration and death or interfere with normal growth and repair. The majority of ACTA1 mutants examined in this study altered the serum response factor signalling pathway, indicatin
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| Contact: Dianne Stilwell diannestilwell@me.com 44-020-897-76510 Biochemical Journal Source:Eurekalert |
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