D.P.14 Mining modifier genes for skeletal muscle actin diseases

Abstract

Actin and myosin are the most important muscle proteins: they generate the force of muscle contraction. Mutations of the skeletal muscle actin gene (ACTA1) cause congenital myopathies, whose commonest presentation is severe, with death within the first year of birth. However, some cases have a mild adult-onset disease suggesting other, modifier genes may be protective. In order to discover such genes, we are using The Collaborative Cross (CC). The CC is a revolutionary genetic resource, part developed at the Western Australian Institute for Medical Research. The CC is a genetic reference population of hundreds of mouse lines descended from eight very diverse founder strains allowing high resolution mapping of genes for traits of interest. Our approach is to cross Acta1 null mice, which usually die by 9days post-natal and are models of human patients with recessive ACTA1 disease, with a large panel of CC mouse strains. We will determine if any of the (CC×Acta1 null) mice are protected from the lethal myopathic phenotype, and will then use the dense genetic map (>600,000 polymorphisms) of the strains to determine the locations of modifier gene (s). In addition, we are using The CC to “mine” genetic loci associated with cardiac actin (Actc) expression in postnatal skeletal muscle. ACTC is the fetal homologue of ACTA1 in skeletal muscle, but is switched off in this tissue at birth. We previously found that transgenic ACTC expression in postnatal skeletal muscle rescues Acat1 knockout mice, suggesting ACTC could have a therapeutic role for ACTA1 diseases. The CC offers unparalleled ability to find modifier genes, as to do so in humans it would take large populations of patients with the same mutation. If we are successful in this project, we will set a precedent for applying The CC to discover disease modifier genes in any disease with a genetic basis.