G.P.50: Mapping a cardiac actin expression QTL using recombinant inbred mouse models

Cardiac actin (ACTC) is the fetal homologue of skeletal muscle actin (ACTA1), and is switched off at birth in skeletal muscle but remains highly expressed in adult heart and in regenerating muscle. ACTC is 99% identical to ACTA1 protein, differing at only 4 amino acids. We previously showed an ACTC transgene could functionally replace ACTA1 in postnatal skeletal muscle of Acta1 knockout mice that normally die within a few days of birth, indicating that ACTC could have a therapeutic role in skeletal muscle actin diseases. We harnessed the power of two different recombinant inbred (RI) mouse models including BXD and the more recently developed Collaborative Cross (CC), to identify genetic elements controlling Actc expression. RI mice are genetic reference populations consisting of large numbers of inbred mouse strains descended from either 2 (BXD) or 8 (CC) founder strains. Characterization of these strains for a trait of interest allows for the mapping of gene(s) mediating that trait to genomic intervals called quantitative trait loci (QTL). We have identified in both RI sets a highly significant QTL regulating Actc expression in skeletal muscle. This QTL also regulates Actc expression in particular non-skeletal muscle tissues (eye and lung). Identification of the regulatory genetic element may provide a target for modifying expression of cardiac actin by therapeutic intervention. Cardiac actin (ACTC) is the fetal homologue of skeletal muscle actin (ACTA1), and is switched off at birth in skeletal muscle but remains highly expressed in adult heart and in regenerating muscle. ACTC is 99% identical to ACTA1 protein, differing at only 4 amino acids. We previously showed an ACTC transgene could functionally replace ACTA1 in postnatal skeletal muscle of Acta1 knockout mice that normally die within a few days of birth, indicating that ACTC could have a therapeutic role in skeletal muscle actin diseases. We harnessed the power of two different recombinant inbred (RI) mouse models including BXD and the more recently developed Collaborative Cross (CC), to identify genetic elements controlling Actc expression. RI mice are genetic reference populations consisting of large numbers of inbred mouse strains descended from either 2 (BXD) or 8 (CC) founder strains. Characterization of these strains for a trait of interest allows for the mapping of gene(s) mediating that trait to genomic intervals called quantitative trait loci (QTL). We have identified in both RI sets a highly significant QTL regulating Actc expression in skeletal muscle. This QTL also regulates Actc expression in particular non-skeletal muscle tissues (eye and lung). Identification of the regulatory genetic element may provide a target for modifying expression of cardiac actin by therapeutic intervention.