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MHC-α is a 224 kDa protein composed of 1939 amino acids.[3][4] The MYH6 gene is located on chromosome 14q12, approximately ~4kb downstream of the MYH7 gene encoding the other major cardiac muscle isoform of myosin heavy chain, MHC-β. MHC-α is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle; it is the predominant isoform expressed in human cardiac atria,[5] and the lesser expressed isoform (7%) expressed in human cardiac ventricles.[6] MHC-α is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-α head non-covalently binds two light chains, atrial essential light chain (MYL4) and atrial regulatory light chain (MYL7).[7] Approximately 300 myosin molecules constitute one thick filament.[8]
Function
MHC-α isoform is abundantly expressed in both cardiac atria and cardiac ventricles during embryonic development. Following birth, cardiac ventricles predominantly express the MHC-βisoform and cardiac atria predominantly express the MHC-α isoform.[5]
The two isoforms of cardiac MHC, α and β, display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β.[7][9]
It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards,[10] then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.[11]
Mutations in MYH6 cause atrial septal defect.[14] One underlying mutation is a missense substitution at Ile820Asn, which alters the association of alpha-myosin heavy chain with regulatory light chain. MYH6 has been shown to be the predominant sarcomeric disease gene for secundum-type atrial septal defects.[15] Additional studies unveiled an association between MYH6 mutations and a wide array of cardiac malformations in addition to atrial septal defect, including one non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations.[16]
MYH6 has also been identified as a susceptibility gene for sick sinus syndrome. A missense mutation at Arg721Trp was identified as conferring a lifetime risk of 50% for carriers.[17] An in-frame 3-bp deletion mutation in MYH6, in which one residue in MHC-α is removed, enhances the binding of MHC-α to myosin binding protein-C and disrupts normal sarcomere function and cardiac atrialconduction velocity.[18]
Cardiomyopathy from mutation R403Q
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.[19] More than half of affected people die by the age of 40 because of HCM due to R403Q.[19] The R403Q mutation interferes with the beta-myosin heavy chain and therefore greatly hinders the functionality of the heart muscle.[20] Specifically, the affected muscle cells have slower contractile velocities, have depressed actin-activated ATPase rates, and have increased stiffness.[20]
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.[20] 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.[19][20] 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.
Myh6 knockdown as a therapy for HCM
HCM is an autosomal dominant disease and conventional treatments are ineffective.[21] Gene therapy is currently being investigated as a possible treatment option. Myh6 gene is a possible target for gene therapy.[21] 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 knockdown mice.[21] The proposed mechanism for this is the expression of a more normalized ratio of α-myosin chain to β-myosin chain proteins.[20] This enables proper assembly of myofibrils and thus, more organized sarcomeres.[20] 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.
References
↑Tanigawa G, Jarcho JA, Kass S, Solomon SD, Vosberg HP, Seidman JG, Seidman CE (Sep 1990). "A molecular basis for familial hypertrophic cardiomyopathy: an alpha/beta cardiac myosin heavy chain hybrid gene". Cell. 62 (5): 991–8. doi:10.1016/0092-8674(90)90273-H. PMID2144212.
↑ 5.05.1Schiaffino S, Reggiani C (Apr 1996). "Molecular diversity of myofibrillar proteins: gene regulation and functional significance". Physiological Reviews. 76 (2): 371–423. PMID8618961.
↑Miyata S, Minobe W, Bristow MR, Leinwand LA (Mar 2000). "Myosin heavy chain isoform expression in the failing and nonfailing human heart". Circulation Research. 86 (4): 386–90. doi:10.1161/01.res.86.4.386. PMID10700442.
↑Tyska MJ, Warshaw DM (Jan 2002). "The myosin power stroke". Cell Motility and the Cytoskeleton. 51 (1): 1–15. doi:10.1002/cm.10014. PMID11810692.
↑Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE (Jan 2002). "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly". Circulation. 105 (4): 446–51. doi:10.1161/hc0402.102990. PMID11815426.
↑Carniel E, Taylor MR, Sinagra G, Di Lenarda A, Ku L, Fain PR, Boucek MM, Cavanaugh J, Miocic S, Slavov D, Graw SL, Feiger J, Zhu XZ, Dao D, Ferguson DA, Bristow MR, Mestroni L (Jul 2005). "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy". Circulation. 112 (1): 54–9. doi:10.1161/CIRCULATIONAHA.104.507699. PMID15998695.
↑Granados-Riveron JT, Ghosh TK, Pope M, Bu'Lock F, Thornborough C, Eason J, Kirk EP, Fatkin D, Feneley MP, Harvey RP, Armour JA, David Brook J (Oct 2010). "Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects". Human Molecular Genetics. 19 (20): 4007–16. doi:10.1093/hmg/ddq315. PMID20656787.
↑Holm H, Gudbjartsson DF, Sulem P, Masson G, Helgadottir HT, Zanon C, Magnusson OT, Helgason A, Saemundsdottir J, Gylfason A, Stefansdottir H, Gretarsdottir S, Matthiasson SE, Thorgeirsson GM, Jonasdottir A, Sigurdsson A, Stefansson H, Werge T, Rafnar T, Kiemeney LA, Parvez B, Muhammad R, Roden DM, Darbar D, Thorleifsson G, Walters GB, Kong A, Thorsteinsdottir U, Arnar DO, Stefansson K (Apr 2011). "A rare variant in MYH6 is associated with high risk of sick sinus syndrome". Nature Genetics. 43 (4): 316–20. doi:10.1038/ng.781. PMC3066272. PMID21378987.
↑Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N (Apr 2015). "Novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome". Circulation: Arrhythmia and Electrophysiology. 8 (2): 400–8. doi:10.1161/CIRCEP.114.002534. PMID25717017.
↑ 19.019.119.2Tyska MJ, Hayes E, Giewat M, Seidman CE, Seidman JG, Warshaw DM (Apr 2000). "Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy". Circulation Research. 86 (7): 737–44. doi:10.1161/01.res.86.7.737. PMID10764406.
↑ 20.020.120.220.320.420.5Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG (Sep 1990). "A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation". Cell. 62 (5): 999–1006. doi:10.1016/0092-8674(90)90274-i. PMID1975517.
Matsuoka R, Beisel KW, Furutani M, Arai S, Takao A (Dec 1991). "Complete sequence of human cardiac alpha-myosin heavy chain gene and amino acid comparison to other myosins based on structural and functional differences". American Journal of Medical Genetics. 41 (4): 537–47. doi:10.1002/ajmg.1320410435. PMID1776652.
Brand NJ, Dabhade N, Yacoub M, Barton PJ (Sep 1991). "Determination of the 5' exon structure of the human cardiac alpha-myosin heavy chain gene". Biochemical and Biophysical Research Communications. 179 (3): 1255–8. doi:10.1016/0006-291X(91)91707-J. PMID1930170.
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Matsuoka R, Yoshida MC, Kanda N, Kimura M, Ozasa H, Takao A (Feb 1989). "Human cardiac myosin heavy chain gene mapped within chromosome region 14q11.2----q13". American Journal of Medical Genetics. 32 (2): 279–84. doi:10.1002/ajmg.1320320234. PMID2494889.
Epp TA, Dixon IM, Wang HY, Sole MJ, Liew CC (Dec 1993). "Structural organization of the human cardiac alpha-myosin heavy chain gene (MYH6)". Genomics. 18 (3): 505–9. doi:10.1016/S0888-7543(11)80006-6. PMID8307559.
Heidkamp MC, Russell B (Jul 2001). "Calcium not strain regulates localization of alpha-myosin heavy chain mRNA in oriented cardiac myocytes". Cell and Tissue Research. 305 (1): 121–7. doi:10.1007/s004410100400. PMID11512664.
Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE (Jan 2002). "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly". Circulation. 105 (4): 446–51. doi:10.1161/hc0402.102990. PMID11815426.
Gupta M, Sueblinvong V, Raman J, Jeevanandam V, Gupta MP (Nov 2003). "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". The Journal of Biological Chemistry. 278 (45): 44935–48. doi:10.1074/jbc.M307696200. PMID12933792.
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Carniel E, Taylor MR, Sinagra G, Di Lenarda A, Ku L, Fain PR, Boucek MM, Cavanaugh J, Miocic S, Slavov D, Graw SL, Feiger J, Zhu XZ, Dao D, Ferguson DA, Bristow MR, Mestroni L (Jul 2005). "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy". Circulation. 112 (1): 54–9. doi:10.1161/CIRCULATIONAHA.104.507699. PMID15998695.
Narolska NA, Eiras S, van Loon RB, Boontje NM, Zaremba R, Spiegelen Berg SR, Stooker W, Huybregts MA, Visser FC, van der Velden J, Stienen GJ (2006). "Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium". Journal of Muscle Research and Cell Motility. 26 (1): 39–48. doi:10.1007/s10974-005-9005-x. PMID16088376.
