Functional Comparison Of Homologous Mutations In Human Beta, Perinatal, And Embryonic Muscle Myosin Isoforms

Fetal skeletal muscle cells co-express three muscle myosin isoforms: beta, perinatal, and embryonic myosin. The perinatal and embryonic myosin genes are downregulated at birth, while beta myosin expression persists in adult slow skeletal muscles but is downregulated in adult fast skeletal muscles. A conserved arginine residue in the core of the motor domain may be mutated in each of these isoforms, and results in distinct clinical phenotypes depending on the isoform in which it is expressed. Mutation of the perinatal and embryonic isoforms leads to the Distal Arthrogryposis syndromes: Trismus Pseudocamptodactyly (TPS) and Freeman Sheldon Syndrome (FSS), respectively. Surprisingly, mutation of the beta isoform does not result in a skeletal muscle phenotype, however, it does lead to hypertrophic cardiomyopathy (HCM) as beta myosin is the dominant isoform expressed in the human heart. In the work presented here, we compare the in vitro protein function of wildtype and mutant human myosins to help elucidate the unique pathologies of four homologous mutations, and gain insight into the different roles of each myosin isoform during the development of skeletal muscles. Measurement of actin-activated ATPase, actin motility, and single molecule force production show differences between the three wildtype isoforms. The effect of the homologous mutations on wildtype protein function show drastic differences in severity which do not correlate with the severity of the resulting clinical phenotype.