Abstract 263: Defective Perinatal Myosin Produces Nemaline Myopathy And Embryonic Lethality
Cardiac myxomas, the most common primary cardiac tumor, can occur in a familial disorder referred to as Carney complex (CNC), in which cardiac myxomas occur in the setting of spotty skin pigmentation, extracardiac myxomas, endocrinopathy, and congenital heart defects. In individuals with a rare CNC variant (typical CNC findings along with the limb contracture syndrome trismus pseudocamptodactyly), we recently identified a R674C missense mutation in the MYH8 gene encoding the perinatal isoform of myosin heavy chain (MyHCpn). MyHCpn was previously thought to be an exclusively skeletal muscle isoform, and its contributions to both heart and skeletal muscle still remain unknown. We hypothesized that normal MyHCpn expression is required for appropriate heart and skeletal muscle development and that MyHCpn mutation modifies embryonic cell proliferation/survival to promote tumorigenesis. To determine if MyHCpn can participate in cardiac muscle development, we defined Myh8 expression patterns during mouse and chick cardiogenesis. Myh8 expression is evident in all cardiac chambers by ED 10.5 in the mouse and by HH 27–28 in the chick. However, by ED 14.5 in the mouse and HH 34–35 in the chick, cardiac Myh8 becomes largely restricted to the atria. Atrial expression is then gradually inactivated, and after birth only rare residual Myh8 positive cells are seen in atria and ventricles. To study further the role of defective MyHCpn in mammalian development, we established a genetically engineered mouse line carrying the orthologue of the R674C mutant MYH8 allele by homologous recombination. Myh8 R674Q/R674Q homozygous mice are growth retarded and die in utero. Thus, MyHCpn is required for normal embryogenesis. Myh8 R674Q/+ heterozygotes appear grossly normal but microscopic examination of skeletal muscle reveals the presence of nemaline rods. Nemaline rods have been reported in cardiac and skeletal myopathies caused by mutations in other sarcomeric proteins. Comparison of the murine histology with a skeletal muscle biopsy from a patient carrying R674Q MYH8 reveals that humans with this MYH8 mutation also exhibit nemaline myopathy. These studies provide the first insights into a hitherto unsuspected role of MyHCpn in mammalian growth and development.