C.I.3 Actin-related disorders

Abstract

Skeletal muscle alpha-actin (ACTA1) is one of the two most important proteins, with myosin, in muscle contraction. ACTA1 mutations cause congenital myopathies with multiple pathologies including actin aggregates, nemaline and intranuclear bodies, fibre type disproportion, caps, core-like areas and zebra bodies. There are now ≈200 different ACTA1 mutations known (http://www.dmd.nl/nmdb2/home.php?select_db=ACTA1). ACTA1 mutations may cause either dominant or recessive disease. Age of onset varies from in utero to adulthood. However, the majority of patients have severe disease frequently resulting in death before age one. Most severely affected patients have de novo dominant mutations, though others may have recessive disease. Dominantly inherited ACTA1 is generally milder. Disease severity may vary even amongst family members, indicating there are modifiers of ACTA1 disease severity. Some mildly affected parents of severely affected children are somatic mosaics for the family mutation. The modifying factor in these parents is therefore the mutant protein load. Recessive ACTA1 mutations are genetic or functional null mutations, nevertheless, recessive patients may have milder disease than patients with de novo dominant mutations. A modifier of severity in recessive patients is the level of retention of the foetal (cardiac) actin isoform in skeletal muscle. Recently it was shown ACTA1 mutation may not only cause classic hypotonic congenital myopathy, but also hypertonic nemaline myopathy. The extreme conservation of actin, means animal models from nematode to mouse are relevant to analyzing the pathophysiology of ACTA1 mutations. To date, despite skeletal muscle actin being a highly studied protein, there is no consensus on the disease-mechanism for dominant ACTA1 mutations. There are anecdotal reports and now mouse model studies, supporting the use of l-tyrosine as a therapeutic for ACTA1 diseases, but no full clinical trial has been performed.