Poster Presentation 6th Australian Health and Medical Research Congress 2012

Identifying modifier genes – using skeletal muscle actin disease as a model (#468)

Jordan Boutilier 1 , Elyshia McNamara 1 , Royston Ong 1 , Nigel G Laing 1 , Grant E Morahan 1 , Kristen Nowak 1
  1. Western Australia Institute for Medical Research and the Centre for Medical Research, University Of Western Australia , Perth, WA, Australia

Actin and myosin interact during muscle contraction. Mutations causing human disease affecting the heart, and/or skeletal muscles occur in multiple actin and myosin isoforms.  Skeletal muscle actin gene 
(ACTA1) mutations cause multiple congenital myopathies, mostly with a severe phenotype causing death within 1 year of life. However, some patients even within the same family have a mild disease, suggesting modifier genes affect disease severity. In order to discover such genes, we are using The
 Collaborative Cross (CC), a revolutionary genetic resource. It consists of hundreds of
 mouse lines descended from eight genetically diverse founder strains, allowing
 high resolution mapping of genes for traits of interest. We previously performed proof of principle experiments using Acta1 knock-out mice (all die by 9 days postnatal)
, good models of some human patients with recessive ACTA1 mutations. By transgenesis, we showed replacing absent skeletal muscle actin protein with cardiac actin (the predominant fetal isoform in skeletal muscles) in postnatal skeletal muscles of Acta1 knock-out mice facilitated survival into old age.

Our aim now is to utilize the power of the CC to identify genetic factors involved in modifying cardiac actin expression in postnatal muscles in humans.  Already we have determined significant variation in the relative levels of cardiac actin expression in mature skeletal muscles across multiple CC mouse strains (>40-fold), and are using the genetic power of The CC to help narrow down modifying loci, one that could potentially become a therapeutic target. In addition, we are crossing Acta1 knock-out mice (disease model) with numerous CC strains, to determine if any resulting Acta1-/- offspring can survive beyond 9 days.  This approach may yield yet other genetic modifiers influencing disease severity. We are also embarking on applying The CC to discover modifier genes for heart disease caused by dominant cardiac actin mutations.