Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located ~4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin.
Hypertrophic cardiomyopathy (HCM) is a cardiac disease that has some characteristic abnormalities including hypertrophy of the septal wall, disorganized cardiac myocytes, and increase fibrosis within the myocardium. The majority of familial HCM cases have been linked to a mutation in beta-myosin heavy chains converting a single amino acid from an arginine to a glutamine at the 403rd position. More than half of affected people die by the age of 40 because of HCM due to R403Q. The R403Q mutation interferes with the beta-myosin heavy chain and therefore greatly hinders the functionality of the heart muscle. Specifically, the affected muscle cells have slower contractile velocities, have depressed actin-activated ATPase rates, and have increased stiffness.
Due to the fact that the cause of the R403Q mutation lies within the region that encodes for the globular myosin head, alterations in the myosin head structure greatly impairs its ability to strongly interact with actin and form a stable cross-bridge. The development of HCM is multifaceted, but the R403Q mutation is one of the most influential risk factors. Of the hundreds of pathogenic mutations that give rise to HCM, R403Q mutations in myosin heavy chain genes are present in over half of them. Since HCM is such a debilitating disease, investigation into possible therapeutic approaches to treat some of the causes of HCM- or at the very least provide palliative care for people affected by this condition- is of extreme importance.
HCM is an autosomal dominant disease and conventional treatments are ineffective. Gene therapy is currently being investigated as a possible treatment option. Myh6 gene is a possible target for gene therapy. Infected with adeno-associated vectors carrying the siRNA to silence the mutant Mhy6 gene, inhibited expression of R403Q myosin postponed development of HCM for 6 months. Without the dysfunctional myosin protein the heart functioned more efficiently and this prevents the development of myocyte hypertrophy as a compensatory mechanism. Not only was there an absence of HCM, but fibrosis and myocyte disorganization was greatly reduced in the knockout mice. The proposed mechanism for this is the expression of a more normalized ratio of α-myosin chain to β-myosin chain proteins. This enables proper assembly of myofibrils and thus, more organized sarcomeres. It should be noted, however, that all of the mice in the study developed HCM after 11 months and that the gene therapy was only temporarily therapeutic.
^ abcTyska MJ, Hayes E, Giewat M, Seidman CE, Seidman JG, Warshaw DM (2000). "Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy". Circ. Res.86 (7): 737–44. PMID10764406.
^ abcdefGeisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG (1990). "A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation". Cell62 (5): 999–1006. PMID1975517.
^ abcJiang J, Wakimoto H, Seidman JG, Seidman CE (2013). "Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy". Science342 (6154): 111–4. doi:10.1126/science.1236921. PMID24092743.
Matsuoka R, Beisel KW, Furutani M, et al. (1992). "Complete sequence of human cardiac alpha-myosin heavy chain gene and amino acid comparison to other myosins based on structural and functional differences.". Am. J. Med. Genet.41 (4): 537–47. doi:10.1002/ajmg.1320410435. PMID1776652.
Brand NJ, Dabhade N, Yacoub M, Barton PJ (1991). "Determination of the 5' exon structure of the human cardiac alpha-myosin heavy chain gene.". Biochem. Biophys. Res. Commun.179 (3): 1255–8. doi:10.1016/0006-291X(91)91707-J. PMID1930170.
Matsuoka R, Yoshida MC, Kanda N, et al. (1989). "Human cardiac myosin heavy chain gene mapped within chromosome region 14q11.2----q13". Am. J. Med. Genet.32 (2): 279–84. doi:10.1002/ajmg.1320320234. PMID2494889.
Heidkamp MC, Russell B (2002). "Calcium not strain regulates localization of alpha-myosin heavy chain mRNA in oriented cardiac myocytes". Cell Tissue Res.305 (1): 121–7. doi:10.1007/s004410100400. PMID11512664.
Niimura H, Patton KK, McKenna WJ, et al. (2002). "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly". Circulation105 (4): 446–51. doi:10.1161/hc0402.102990. PMID11815426.
Gupta M, Sueblinvong V, Raman J, et al. (2004). "Single-stranded DNA-binding proteins PURalpha and PURbeta bind to a purine-rich negative regulatory element of the alpha-myosin heavy chain gene and control transcriptional and translational regulation of the gene expression. Implications in the repression of alpha-myosin heavy chain during heart failure". J. Biol. Chem.278 (45): 44935–48. doi:10.1074/jbc.M307696200. PMID12933792.
Ching YH, Ghosh TK, Cross SJ, et al. (2005). "Mutation in myosin heavy chain 6 causes atrial septal defect". Nat. Genet.37 (4): 423–8. doi:10.1038/ng1526. PMID15735645.
Carniel E, Taylor MR, Sinagra G, et al. (2006). "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy". Circulation112 (1): 54–9. doi:10.1161/CIRCULATIONAHA.104.507699. PMID15998695.
Narolska NA, Eiras S, van Loon RB, et al. (2006). "Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium". J. Muscle Res. Cell. Motil.26 (1): 39–48. doi:10.1007/s10974-005-9005-x. PMID16088376.