MYH6 explained

Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene.[1] [2] This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.

Structure

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-β isoform 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]

Clinical significance

The first mutation identified in MYH6 by Niimura et al. was found in a patient population with late-onset hypertrophic cardiomyopathy. An Arg to Gln variant was found at position 795 (Arg795Gln). This mutation was located in a region of MHC-α shown to be important for binding essential light chain.[12] Subsequent studies have also found additional mutations in MYH6 linked to both hypertrophic cardiomyopathy and dilated cardiomyopathy.[13]

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 atrial conduction 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] All of the mice in the study developed HCM after 11 months and that the gene therapy was only temporarily therapeutic.

Further reading

External links

Notes and References

  1. Tanigawa G, Jarcho JA, Kass S, Solomon SD, Vosberg HP, Seidman JG, Seidman CE . A molecular basis for familial hypertrophic cardiomyopathy: an alpha/beta cardiac myosin heavy chain hybrid gene . Cell . 62 . 5 . 991–8 . Sep 1990 . 2144212 . 10.1016/0092-8674(90)90273-H . 140204275 .
  2. Web site: Entrez Gene: MYH6 myosin, heavy chain 6, cardiac muscle, alpha (cardiomyopathy, hypertrophic 1).
  3. Web site: Protein sequence of human MYH6 (Uniprot ID: P13533). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 10 August 2015.
  4. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
  5. Schiaffino S, Reggiani C . Molecular diversity of myofibrillar proteins: gene regulation and functional significance . Physiological Reviews . 76 . 2 . 371–423 . Apr 1996 . 8618961 . 10.1152/physrev.1996.76.2.371 . free .
  6. Miyata S, Minobe W, Bristow MR, Leinwand LA . Myosin heavy chain isoform expression in the failing and nonfailing human heart . Circulation Research . 86 . 4 . 386–90 . Mar 2000 . 10700442 . 10.1161/01.res.86.4.386. free .
  7. Palmer BM . Thick filament proteins and performance in human heart failure . Heart Failure Reviews . 10 . 3 . 187–97 . Sep 2005 . 16416042 . 10.1007/s10741-005-5249-1 . 20691228 .
  8. Harris SP, Lyons RG, Bezold KL . In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament . Circulation Research . 108 . 6 . 751–64 . Mar 2011 . 21415409 . 10.1161/CIRCRESAHA.110.231670 . 3076008.
  9. Alpert NR, Brosseau C, Federico A, Krenz M, Robbins J, Warshaw DM . Molecular mechanics of mouse cardiac myosin isoforms . American Journal of Physiology. Heart and Circulatory Physiology . 283 . 4 . H1446–54 . Oct 2002 . 12234796 . 10.1152/ajpheart.00274.2002 .
  10. McKillop DF, Geeves MA . Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament . Biophysical Journal . 65 . 2 . 693–701 . Aug 1993 . 8218897 . 10.1016/S0006-3495(93)81110-X . 1225772. 1993BpJ....65..693M .
  11. Tyska MJ, Warshaw DM . The myosin power stroke . Cell Motility and the Cytoskeleton . 51 . 1 . 1–15 . Jan 2002 . 11810692 . 10.1002/cm.10014 .
  12. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE . Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly . Circulation . 105 . 4 . 446–51 . Jan 2002 . 11815426 . 10.1161/hc0402.102990. free .
  13. 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 . Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy . Circulation . 112 . 1 . 54–9 . Jul 2005 . 15998695 . 10.1161/CIRCULATIONAHA.104.507699 . free .
  14. Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD . Mutation in myosin heavy chain 6 causes atrial septal defect . Nature Genetics . 37 . 4 . 423–8 . Apr 2005 . 15735645 . 10.1038/ng1526 . free .
  15. Posch MG, Waldmuller S, Müller M, Scheffold T, Fournier D, Andrade-Navarro MA, De Geeter B, Guillaumont S, Dauphin C, Yousseff D, Schmitt KR, Perrot A, Berger F, Hetzer R, Bouvagnet P, Özcelik C . Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects . PLOS ONE . 6 . 12 . e28872 . 2011 . 22194935 . 10.1371/journal.pone.0028872 . 3237499. 2011PLoSO...628872P . free .
  16. 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 . Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects . Human Molecular Genetics . 19 . 20 . 4007–16 . Oct 2010 . 20656787 . 10.1093/hmg/ddq315 . free .
  17. 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 . A rare variant in MYH6 is associated with high risk of sick sinus syndrome . Nature Genetics . 43 . 4 . 316–20 . Apr 2011 . 21378987 . 10.1038/ng.781 . 3066272.
  18. Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N . Novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome . Circulation: Arrhythmia and Electrophysiology . 8 . 2 . 400–8 . Apr 2015 . 25717017 . 10.1161/CIRCEP.114.002534 . 1943856 .
  19. Tyska MJ, Hayes E, Giewat M, Seidman CE, Seidman JG, Warshaw DM . Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy . Circulation Research . 86 . 7 . 737–44 . Apr 2000 . 10764406 . 10.1161/01.res.86.7.737 . free .
  20. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG . A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation . Cell . 62 . 5 . 999–1006 . Sep 1990 . 1975517 . 10.1016/0092-8674(90)90274-i . 45182243 .
  21. Jiang J, Wakimoto H, Seidman JG, Seidman CE . Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy . Science . 342 . 6154 . 111–4 . Oct 2013 . 24092743 . 4100553 . 10.1126/science.1236921 . 2013Sci...342..111J .

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