SEMINAR: Investigation of Sarcomeric Protein Diseases

William completed his undergraduate biomedical science degree at UWA before joining the Laing laboratory at WAIMR as an honours student, investigating the characteristics of actin (ACTA1) mutations in a cohort of Japanese nemaline myopathy patients. Staying on in the Laing laboratory for his PhD project, William began investigating the effects of disease-causing mutations in other sarcomeric proteins with a focus on slow/-cardiac myosin (-MyHC), encoded by MYH7. -MyHC is a molecular motor, fundamental to the contractile and structural properties of the skeletal muscle sarcomere. Mutations in MYH7 cause a number of different disease phenotypes including Laing early onset distal myopathy (MPD1), myosin storage myopathy (MSM), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Mutations causing HCM and DCM are spread across the gene while mutations causing MPD1 and MSM are confined to exons encoding the C-terminal light-meromyosin (LMM) region of -MyHC. How mutations located in similar regions of the same gene are able to cause such a wide phenotypic range of diseases is as yet unknown. During his PhD project William identified a number of novel and previously known MYH7 mutations, broadening the phenotypic and genetic heterogeneity of MYH7 myopathies. Investigation of the in vitro effects of MYH7 mutations by circular dichroism (CD) and cell culture transfection studies resulted in new insights into the pathobiology underlying MYH7 muscle disease.