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Gene Review

MYH6  -  myosin, heavy chain 6, cardiac muscle, alpha

Homo sapiens

Synonyms: ASD3, CMD1EE, CMH14, MYHC, MYHCA, ...
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Disease relevance of MYH6

  • A human cardiac myosin heavy-chain (MHC) gene, cloned in a charon 4A phage, was isolated using two rat cardiac pCMHC DNA clones (pCMHC26: alpha-MHC type; and pCMHC5: beta-MHC type) as probes and shown to correspond to cardiac myosin heavy-chain of the alpha-type [1].
  • Atrial fibrillation was accompanied by a significant shift from the fast alpha-MHC isoform to the slow beta-MHC isoform, whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform [2].
  • Cardiac myosin heavy chain (myhca) is the major autoantigen associated with autoimmune myocarditis both in humans and in experimental autoimmune myocarditis (EAM) in mice [3].
  • CONCLUSION: Cardiac hypertrophy and failure cause downregulation of the endogenous alpha-MHC as well as cardiac specific overexpression of the transgene directed by an alpha-MHC promoter [4].
  • These results suggest that even mild chronic myocardial thyrotoxicosis, such as may occur in human hyperthyroidism, can cause tachycardia and associated changes in high energy phosphate compounds independent of an increase in SERCA II and alpha-MHC [5].

High impact information on MYH6


Chemical compound and disease context of MYH6


Biological context of MYH6

  • Based on these data, the four loci were mapped within an approximately 600-kb region with the following centromere to telomere order: D14S283, D14S990, MYH6, and MYH7 [12].
  • Our previous report demonstrated that two human cardiac alpha- and beta-myosin heavy-chains (MHCs) which correspond to MYH6 and MYH7 respectively, according to Human Gene Mapping nomenclature, were mapped to human chromosome 14 and that human cardiac and skeletal MHC genes do not cosegregate [13].
  • CONCLUSIONS: This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM [14].
  • All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population [14].
  • Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands) [14].

Anatomical context of MYH6

  • Together, these results reveal that (i) PUR proteins participate in transcriptional as well as translational regulation of alpha-MHC expression in cardiac myocytes and (ii) ERP may be involved in cardiac-restricted expression of the alpha-MHC gene by preventing its expression in non-muscle cells [15].
  • The alpha-MHC type cardiac genomic DNA clone and the beta-MHC type cardiac cDNA clone were used as probes in the Southern analysis of human genomic DNA from human-Chinese hamster or human-mouse somatic cell hybrids [16].
  • Constructs encoding wild-type rat alpha MHC and seven corresponding FHC missense mutants were transfected into COS cells [8].
  • In the current study, we evaluated two methods for the enumeration and phenotypic characterization of myhca-specific CD4+ T cells during the course of EAM [3].
  • Concomitant surface marker analysis in the CFC assay revealed the prototypical effector phenotype of myhca-specific Th1 cells during the acute phase of the disease [3].

Associations of MYH6 with chemical compounds

  • No modifications were observed in myosin function evaluated by in vitro motility assay, whereas the administration of L-thyroxine (100 micrograms/kg intraperitoneally daily) to CMPH was able to reinduce the ventricular expression of the alpha MHC isoform (5-fold increase) [17].
  • After birth, thyroid hormone induces expression of alpha-MHC mRNA and inhibits expression of the beta-MHC gene [18].
  • Furthermore, ascorbic acid induced the expression of cardiac genes, including GATA4, alpha-MHC, and beta-MHC in untransfected ES cells in a developmentally controlled manner [19].
  • The series includes L243 IgG1 (alpha-MHC Class II) lacking a CH3 domain pair (DeltaCH3-IgG1), single-chain Fv fusion proteins with Fc or a hinge-CH2 domain, Fc with/out a hinge, and a single CH2 domain [20].
  • Treatment of hypothyroid rats with amiodarone had no significant effect on beta-MHC or Spot 14 mRNAs, but a further reduction in alpha-MHC mRNA, compared with the untreated hypothyroid state, was evident [21].

Physical interactions of MYH6


Regulatory relationships of MYH6


Other interactions of MYH6

  • Layer-specific differential expression was validated at both mRNA and protein level for MYH3, MYH6, and ACTN3 [24].
  • The positive TRE for T(3)-stimulation of alpha-MHC is an imperfect direct repeat located in the proximal promoter of the gene [18].
  • A molecular mechanism by which contractile function modulates alpha-MHC transcriptional activity may involve signaling via phosphorylation of USF1 [25].
  • Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC [26].
  • METHODS AND RESULTS: To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha-MHC with increased beta-MHC expression compared with left ventricles from age-matched controls [27].

Analytical, diagnostic and therapeutic context of MYH6


  1. Molecular cloning and chromosomal localization of a gene coding for human cardiac myosin heavy-chain. Matsuoka, R., Chambers, A., Kimura, M., Kanda, N., Bruns, G., Yoshida, M., Takao, A. Am. J. Med. Genet. (1988) [Pubmed]
  2. Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium. Narolska, N.A., Eiras, S., van Loon, R.B., Boontje, N.M., Zaremba, R., Spiegelen Berg, S.R., Stooker, W., Huybregts, M.A., Visser, F.C., van der Velden, J., Stienen, G.J. J. Muscle Res. Cell. Motil. (2005) [Pubmed]
  3. Quantification and characterization of myosin peptide-specific CD4+ T cells in autoimmune myocarditis. Maier, R., Miller, S., Kurrer, M., Krebs, P., de Giuli, R., Kremer, M., Scandella, E., Ludewig, B. J. Immunol. Methods (2005) [Pubmed]
  4. Beta(2)-adrenergic receptor overexpression driven by alpha-MHC promoter is downregulated in hypertrophied and failing myocardium. Sheridan, D.J., Autelitano, D.J., Wang, B., Percy, E., Woodcock, E.A., Du, X.J. Cardiovasc. Res. (2000) [Pubmed]
  5. Type 2 iodothyronin deiodinase transgene expression in the mouse heart causes cardiac-specific thyrotoxicosis. Pachucki, J., Hopkins, J., Peeters, R., Tu, H., Carvalho, S.D., Kaulbach, H., Abel, E.D., Wondisford, F.E., Ingwall, J.S., Larsen, P.R. Endocrinology (2001) [Pubmed]
  6. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Swynghedauw, B. Physiol. Rev. (1986) [Pubmed]
  7. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. Lowes, B.D., Minobe, W., Abraham, W.T., Rizeq, M.N., Bohlmeyer, T.J., Quaife, R.A., Roden, R.L., Dutcher, D.L., Robertson, A.D., Voelkel, N.F., Badesch, D.B., Groves, B.M., Gilbert, E.M., Bristow, M.R. J. Clin. Invest. (1997) [Pubmed]
  8. Functional analysis of myosin missense mutations in familial hypertrophic cardiomyopathy. Straceski, A.J., Geisterfer-Lowrance, A., Seidman, C.E., Seidman, J.G., Leinwand, L.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. Regulation of myosin heavy chain genes in the heart. Morkin, E. Circulation (1993) [Pubmed]
  10. Thyroid hormone regulates expression of a transfected human alpha-myosin heavy-chain fusion gene in fetal rat heart cells. Tsika, R.W., Bahl, J.J., Leinwand, L.A., Morkin, E. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  11. Testosterone, cytochrome P450, and cardiac hypertrophy. Thum, T., Borlak, J. FASEB J. (2002) [Pubmed]
  12. Restriction map of a YAC and cosmid contig encompassing the oculopharyngeal muscular dystrophy candidate region on chromosome 14q11.2-q13. Xie, Y.G., Rochefort, D., Brais, B., Howard, H., Han, F.Y., Gou, L.P., Maciel, P., The, B.T., Larsson, C., Rouleau, G.A. Genomics (1998) [Pubmed]
  13. Human cardiac myosin heavy chain gene mapped within chromosome region 14q11.2----q13. Matsuoka, R., Yoshida, M.C., Kanda, N., Kimura, M., Ozasa, H., Takao, A. Am. J. Med. Genet. (1989) [Pubmed]
  14. Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Carniel, E., Taylor, M.R., Sinagra, G., Di Lenarda, A., Ku, L., Fain, P.R., Boucek, M.M., Cavanaugh, J., Miocic, S., Slavov, D., Graw, S.L., Feiger, J., Zhu, X.Z., Dao, D., Ferguson, D.A., Bristow, M.R., Mestroni, L. Circulation (2005) [Pubmed]
  15. 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. Gupta, M., Sueblinvong, V., Raman, J., Jeevanandam, V., Gupta, M.P. J. Biol. Chem. (2003) [Pubmed]
  16. Molecular cloning and chromosomal localization of a gene coding for human cardiac myosin heavy-chain. Matsuoka, R., Yoshida, M.C., Takao, A. Jpn. Circ. J. (1990) [Pubmed]
  17. Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters. Di Nardo, P., Fiaccavento, R., Natali, A., Minieri, M., Sampaolesi, M., Fusco, A., Janmot, C., Cuda, G., Carbone, A., Rogliani, P., Peruzzi, G. Lab. Invest. (1997) [Pubmed]
  18. Control of cardiac myosin heavy chain gene expression. Morkin, E. Microsc. Res. Tech. (2000) [Pubmed]
  19. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Takahashi, T., Lord, B., Schulze, P.C., Fryer, R.M., Sarang, S.S., Gullans, S.R., Lee, R.T. Circulation (2003) [Pubmed]
  20. Expression and characterization of truncated forms of humanized L243 IgG1. Architectural features can influence synthesis of its oligosaccharide chains and affect superoxide production triggered through human Fcgamma receptor I. Lund, J., Takahashi, N., Popplewell, A., Goodall, M., Pound, J.D., Tyler, R., King, D.J., Jefferis, R. Eur. J. Biochem. (2000) [Pubmed]
  21. Regulation of alpha- and beta-myosin heavy chain messenger RNAs in the rat myocardium by amiodarone and by thyroid status. Franklyn, J.A., Green, N.K., Gammage, M.D., Alhquist, J.A., Sheppard, M.C. Clin. Sci. (1989) [Pubmed]
  22. Regulation of cardiac alpha-myosin heavy chain gene transcription by a contractile-responsive E-box binding protein. Xiao, Q., Ojamaa, K. J. Mol. Cell. Cardiol. (1998) [Pubmed]
  23. Vascular endothelial growth factor promotes cardiomyocyte differentiation of embryonic stem cells. Chen, Y., Amende, I., Hampton, T.G., Yang, Y., Ke, Q., Min, J.Y., Xiao, Y.F., Morgan, J.P. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  24. Layer-specific differences of gene expression in extraocular muscles identified by laser-capture microscopy. Budak, M.T., Bogdanovich, S., Wiesen, M.H., Lozynska, O., Khurana, T.S., Rubinstein, N.A. Physiol. Genomics (2004) [Pubmed]
  25. Role of USF1 phosphorylation on cardiac alpha-myosin heavy chain promoter activity. Xiao, Q., Kenessey, A., Ojamaa, K. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  26. Modulation of in vivo cardiac hypertrophy with insulin-like growth factor-1 and angiotensin-converting enzyme inhibitor: relationship between change in myosin isoform and progression of left ventricular dysfunction. Iwanaga, Y., Kihara, Y., Yoneda, T., Aoyama, T., Sasayama, S. J. Am. Coll. Cardiol. (2000) [Pubmed]
  27. Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression. Kinugawa, K., Minobe, W.A., Wood, W.M., Ridgway, E.C., Baxter, J.D., Ribeiro, R.C., Tawadrous, M.F., Lowes, B.A., Long, C.S., Bristow, M.R. Circulation (2001) [Pubmed]
  28. Complete sequence of human cardiac alpha-myosin heavy chain gene and amino acid comparison to other myosins based on structural and functional differences. Matsuoka, R., Beisel, K.W., Furutani, M., Arai, S., Takao, A. Am. J. Med. Genet. (1991) [Pubmed]
  29. Analysis of sense and naturally occurring antisense transcripts of myosin heavy chain in the human myocardium. Luther, H.P., Podlowski, S., Hetzer, R., Baumann, G. J. Cell. Biochem. (2001) [Pubmed]
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