MYH6
Myosin-6 is a protein that in humans is encoded by the MYH6 gene.[1][2]
Function
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.[2]
Clinical significance
Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3.[2]
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.[3] More than half of affected people die by the age of 40 because of HCM due to R403Q.[3] The R403Q mutation interferes with the beta-myosin heavy chain and therefore greatly hinders the functionality of the heart muscle.[4] Specifically, the affected muscle cells have slower contractile velocities, have depressed actin-activated ATPase rates, and have increased stiffness.[4]
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.[4] 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.[4][3] 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 knockout as a therapy for HCM
HCM is an autosomal dominant disease and conventional treatments are ineffective.[5] Gene therapy is currently being investigated as a possible treatment option. Myh6 gene is a possible target for gene therapy.[5] 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.[5] The proposed mechanism for this is the expression of a more normalized ratio of α-myosin chain to β-myosin chain proteins.[4] This enables proper assembly of myofibrils and thus, more organized sarcomeres.[4] 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 (Oct 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. PMID 2144212.
- ↑ 2.0 2.1 2.2 "Entrez Gene: MYH6 myosin, heavy chain 6, cardiac muscle, alpha (cardiomyopathy, hypertrophic 1)".
- ↑ 3.0 3.1 3.2 Tyska 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. doi:10.1161/01.res.86.7.737. PMID 10764406.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Geisterfer-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". Cell 62 (5): 999–1006. doi:10.1016/0092-8674(90)90274-i. PMID 1975517.
- ↑ 5.0 5.1 5.2 Jiang J, Wakimoto H, Seidman JG, Seidman CE (2013). "Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy". Science 342 (6154): 111–4. doi:10.1126/science.1236921. PMC 4100553. PMID 24092743.
Further reading
- 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. PMID 1776652.
- 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. PMID 1930170.
- Solomon SD, Geisterfer-Lowrance AA, Vosberg HP et al. (1990). "A locus for familial hypertrophic cardiomyopathy is closely linked to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on chromosome 14 at q11-q12.". Am. J. Hum. Genet. 47 (3): 389–94. PMC 1683877. PMID 1975475.
- Ehrlich PH, Moustafa ZA, Ostberg L (1991). "Nucleotide sequence of chimpanzee Fc and hinge regions.". Mol. Immunol. 28 (4–5): 319–22. doi:10.1016/0161-5890(91)90143-8. PMID 2062315.
- 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. PMID 2494889.
- Yamauchi-Takihara K, Sole MJ, Liew J et al. (1989). "Characterization of human cardiac myosin heavy chain genes". Proc. Natl. Acad. Sci. U.S.A. 86 (10): 3504–8. doi:10.1073/pnas.86.10.3504. PMC 287166. PMID 2726733.
- Kurabayashi M, Tsuchimochi H, Komuro I et al. (1988). "Molecular cloning and characterization of human cardiac alpha- and beta-form myosin heavy chain complementary DNA clones. Regulation of expression during development and pressure overload in human atrium". J. Clin. Invest. 82 (2): 524–31. doi:10.1172/JCI113627. PMC 303543. PMID 2969919.
- Saez LJ, Gianola KM, McNally EM et al. (1987). "Human cardiac myosin heavy chain genes and their linkage in the genome". Nucleic Acids Res. 15 (13): 5443–59. doi:10.1093/nar/15.13.5443. PMC 305971. PMID 3037493.
- Epp TA, Dixon IM, Wang HY et al. (1994). "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. PMID 8307559.
- Shoeman RL, Sachse C, Höner B et al. (1993). "Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin". Am. J. Pathol. 142 (1): 221–30. PMC 1886840. PMID 8424456.
- Nakao K, Minobe W, Roden R et al. (1997). "Myosin heavy chain gene expression in human heart failure". J. Clin. Invest. 100 (9): 2362–70. doi:10.1172/JCI119776. PMC 508434. PMID 9410916.
- 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. PMID 11512664.
- Niimura H, Patton KK, McKenna WJ et al. (2002). "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly". Circulation 105 (4): 446–51. doi:10.1161/hc0402.102990. PMID 11815426.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- 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. PMID 12933792.
- Narolska NA, van Loon RB, Boontje NM et al. (2005). "Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue". Cardiovasc. Res. 65 (1): 221–9. doi:10.1016/j.cardiores.2004.09.029. PMID 15621050.
- 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. PMID 15735645.
- Carniel E, Taylor MR, Sinagra G et al. (2006). "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. PMID 15998695.
- 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. PMID 16088376.
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