Alternative titles; symbols
HGNC Approved Gene Symbol: MYH1
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:10,492,307-10,518,542 (from NCBI)
Myosin heavy chains (MYHCs) are ubiquitous actin-based motor proteins that convert the chemical energy derived from hydrolysis of ATP into mechanical force that drives diverse motile processes, including cytokinesis, vesicular transport, and cellular locomotion, in eukaryotic cells. The MYHCs have been divided into 9 to 11 classes. Class II, or 'conventional,' MYHCs include the extensively studied group of sarcomeric MYHCs that self associate to form filaments and function enzymatically to promote contraction in striated (cardiac and skeletal) muscles. Muscle myosin is a heterohexamer consisting of 2 myosin heavy chains and 2 associated nonidentical pairs of myosin light chains. The 7 MYHC isoforms that predominate in mammalian skeletal muscles include 2 developmental isoforms, MYHC-embryonic (MYH3; 160720) and MYHC-perinatal (MYH8; 160741); 3 adult skeletal muscle isoforms, MYHC IIa (MYH2; 160740), MYHC IIb (MYH4; 160742), and MYHC IIx/d (MYH1); and MYHC-beta/slow (MYH7; 160760), which is also expressed in cardiac muscle. MYHC-extraocular (MYH13; 603487) is expressed primarily in extrinsic eye muscles.
By in situ hybridization of human skeletal muscle, Smerdu et al. (1994) detected populations of muscle fibers that expressed only MHC IIx or that coexpressed MHC IIa and MHC IIx. Although some fibers coexpressed MHC-beta/slow and MHC IIa, none coexpressed MHC-beta/slow and MHC IIx. Immunohistochemical analysis identified fibers containing MHC IIa and/or MHC IIx mRNA as fast-twitch type II fibers. Type IIa fibers had more MHC IIa, whereas type IIb fibers had more MHC IIx.
By RT-PCR of human skeletal muscle RNA, Weiss et al. (1999) cloned full-length MHC IIx. MHC IIx shares 94.8% amino acid identity with MHC IIa. All MHC proteins share approximately 100% conservation in the phosphate-binding loop, several helices forming the nucleotide-binding pocket, residues involved in actin binding, residues involved in the stereospecific hydrophobic rigor state interaction of actin with myosin, a cleft that divides the ATP- and actin-binding sites, and a converter domain, or fulcrum, containing 2 conserved cysteines.
Cryoelectron Microscopy
Woodhead et al. (2005) analyzed the structure of a phosphorylation-regulated striated muscle thick filament using cryoelectron microscopy. Three-dimensional reconstruction and atomic fitting studies suggest that the interacting head structure is also present in the filament, and that it may underlie the relaxed state of thick filaments in both smooth and myosin-regulated striated muscles
Leinwand et al. (1983) isolated 4 human myosin heavy chain (MYH) genomic clones that are unique and nonoverlapping. Three contained adult skeletal muscle-specific sequences and 1 contained embryonic muscle-specific sequences. Sarcoplasmic MYH gene(s) have diverged enough from those for smooth muscle and nonmuscle MYH that no cross-hybridization occurs. By hybridization of cloned skeletal myosin heavy chain DNA probes to restriction endonuclease digests of genomic DNA from somatic cell hybrids, Leinwand et al. (1983) showed that at least 3 different sarcomeric myosin heavy chain genes are located on 17pter-p11: 2 adult skeletal muscle genes, MYHSA1 and MYHSA2 (MYH2), and an embryonic gene, MYHSE1 (MYH3). All 3 genes are on mouse chromosome 11, which also carries thymidine kinase (188300) and galactokinase (604313), which are on 17q in man. Rappold and Vosberg (1983) assigned a human myosin heavy chain gene to 17pter-p12 by in situ hybridization.
Edwards et al. (1985) indicated that there are 7 to 13 different mammalian heavy chain genes that are expressed in cardiac and skeletal muscle, smooth muscle, and fetal muscle. In addition, 2 nonmuscle myosin heavy chain genes have been described. Edwards et al. (1985) mapped a fetal skeletal cDNA to 17pter-p11 and found no evidence of myosin heavy chain sequences on other chromosomes. In the mouse, Weydert et al. (1985) showed that embryonic, perinatal, and adult skeletal myosin heavy chain genes are clustered on chromosome 11 near the 'nude' locus. Cardiac myosin heavy chains (see 160710) in the mouse do not segregate with the skeletal myosin heavy chains.
Yoon et al. (1992) isolated 9 YACs containing MYH genes and used them to construct a contiguous set (contig), which encompassed a genetic marker mapped to 17p13.1. Six MYH genes were located within a 500-kb segment. The order of the genes within the cluster did not correspond to the developmental pattern of expression of the individual members. Soussi-Yanicostas et al. (1993) used genomic DNA mapping by pulsed field gel electrophoresis to demonstrate that, in humans, the genes for what they referred to as the embryonic, fetal, fast IIB, and IIX myosin heavy chains and a gene coding for an unidentified striated muscle fast-type myosin heavy chain isoform are contained within a 320-kb SalI genomic fragment. In a study of YAC clones, they found that the embryonic and fetal genes, on the one hand, and the adult fast (IIB, IIX, and unidentified) genes, on the other hand, are contained within 2 different ClaI fragments. They suggested that these results indicated that the genes encoding the 2 developmental forms are adjacent in the human genome and that temporal regulation of the myosin heavy chain genes may be related to their organization within the cluster. These findings probably indicate that the gene MYH8 and MYH4 are in the same gene cluster as MYH1, MYH2, and MYH3 on 17p13.1.
To gain a better understanding of the genomic organization of the skeletal myosin heavy chain genes and the effects of this organization on the regulation, function, and molecular genetics of this multigene family, Weiss et al. (1999) constructed high-resolution physical maps of both human and mouse loci using PCR-based marker content mapping of P1-artificial chromosome clones. Genes encoding 6 myosin heavy chain isoforms were mapped with respect to their linear order and transcriptional orientations within a 350-kb region in both human and mouse. These maps revealed that the order, transcriptional orientation, and relative intergenic distances of these genes have been remarkably conserved. Unlike many clustered gene families, this order does not reflect the known temporal expression patterns of these genes. However, the conservation of gene organization since the divergence of these species approximately 75 to 110 million years ago suggests that the physical organization of these genes may be significant for their regulation and function.
Edwards, Y. H., Parkar, M., Povey, S., West, L. F., Parrington, J. M., Solomon, E. Human myosin heavy chain genes assigned to chromosome 17 using a human cDNA clone as probe. Ann. Hum. Genet. 49: 101-109, 1985. [PubMed: 3000272] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01681.x]
Jandreski, M. A., Sole, M. J., Liew, C.-C. Two different forms of beta myosin heavy chain are expressed in human striated muscle. Hum. Genet. 77: 127-131, 1987. [PubMed: 3653886] [Full Text: https://doi.org/10.1007/BF00272378]
Leinwand, L. A., Fournier, R. E. K., Nadal-Ginard, B., Shows, T. B. Assignment of the sarcomeric myosin heavy chain multigene family to chromosome 17 in humans and chromosome 11 in the mouse. (Abstract) Cytogenet. Cell Genet. 37: 521-522, 1984.
Leinwand, L. A., Fournier, R. E. K., Nadal-Ginard, B., Shows, T. B. Multigene family for sarcomeric myosin heavy chain in mouse and human DNA: localization on a single chromosome. Science 221: 766-769, 1983. [PubMed: 6879174] [Full Text: https://doi.org/10.1126/science.6879174]
Leinwand, L. A., Saez, L., McNally, E., Bernardo, N.-G. Isolation and characterization of human myosin heavy chain genes. Proc. Nat. Acad. Sci. 80: 3716-3720, 1983. [PubMed: 6304733] [Full Text: https://doi.org/10.1073/pnas.80.12.3716]
Rappold, G. A., Vosberg, H.-P. Chromosomal localization of a human myosin heavy-chain gene by in situ hybridization. Hum. Genet. 65: 195-197, 1983. [PubMed: 6654334] [Full Text: https://doi.org/10.1007/BF00286663]
Smerdu, V., Karsch-Mizrachi, I., Campione, M., Leinwand, L., Schiaffino, S. Type IIx myosin heavy chain transcripts are expressed in type IIb fibers of human skeletal muscle. Am. J. Physiol. 267: C1723-C1728, 1994. [PubMed: 7545970] [Full Text: https://doi.org/10.1152/ajpcell.1994.267.6.C1723]
Soussi-Yanicostas, N., Whalen, R. G., Petit, C. Five skeletal myosin heavy chain genes are organized as a multigene complex in the human genome. Hum. Molec. Genet. 2: 563-569, 1993. [PubMed: 8518795] [Full Text: https://doi.org/10.1093/hmg/2.5.563]
Weiss, A., McDonough, D., Wertman, B., Acakpo-Satchivi, L., Montgomery, K., Kucherlapati, R., Leinwand, L., Krauter, K. Organization of human and mouse skeletal myosin heavy chain gene clusters is highly conserved. Proc. Nat. Acad. Sci. 96: 2958-2963, 1999. [PubMed: 10077619] [Full Text: https://doi.org/10.1073/pnas.96.6.2958]
Weiss, A., Schiaffino, S., Leinwand, L. A. Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity. J. Molec. Biol. 290: 61-75, 1999. [PubMed: 10388558] [Full Text: https://doi.org/10.1006/jmbi.1999.2865]
Weydert, A., Daubas, P., Lazaridis, I., Barton, P., Garner, I., Leader, D. P., Bonhomme, F., Catalan, J., Simon, D., Guenet, J. L., Gros, F., Buckingham, M. E. Genes for skeletal muscle myosin heavy chains are clustered and are not located on the same mouse chromosome as a cardiac myosin heavy chain gene. Proc. Nat. Acad. Sci. 82: 7183-7187, 1985. [PubMed: 3864153] [Full Text: https://doi.org/10.1073/pnas.82.21.7183]
Woodhead, J. L., Zhao, F.-Q., Craig, R., Egelman, E. H., Alamo, L., Padron, R. Atomic model of a myosin filament in the relaxed state. Nature 436: 1195-1199, 2005. [PubMed: 16121187] [Full Text: https://doi.org/10.1038/nature03920]
Yoon, S.-J., Seiler, S. H., Kucherlapati, R., Leinwand, L. Organization of the human skeletal myosin heavy chain gene cluster. Proc. Nat. Acad. Sci. 89: 12078-12082, 1992. [PubMed: 1465443] [Full Text: https://doi.org/10.1073/pnas.89.24.12078]