Alternative titles; symbols
HGNC Approved Gene Symbol: MYF6
Cytogenetic location: 12q21.31 Genomic coordinates (GRCh38): 12:80,707,634-80,709,474 (from NCBI)
Braun et al. (1990) detected the MYF6 gene, a novel member of the human gene family of muscle determination factors, by its highly conserved sequence coding for a putative helix-loop-helix domain. This sequence motif is a common feature of all myogenic factors and other regulatory proteins.
By a panel of human/rodent somatic hybrid cells lines, Braun et al. (1990) mapped MYF6 to chromosome 12. In situ hybridization suggested close localization to MYF5 (159990). When a human genomic library was screened for the MYF6 gene, 2 of the recombinant lambda-phages isolated contained all or parts of both MYF6 and MYF5. Restriction analysis indicated that the MYF6 gene is located upstream of MYF5 in the same orientation, with a distance of about 6.5 kb separating the genes.
Cupelli et al. (1996) mapped the MYF5/MYF6 gene cluster to 12q21 between D12S350 and D12S106 by hybridization to YACs. The 2 MYF genes could not be ordered with respect to each other. This was not surprising since Braun et al. (1990) found that the 2 genes lie within 6.5 kb of each other.
Bureau et al. (1995) found that the mouse Myf6 gene is in a region of mouse chromosome 10 that shows considerable homology of synteny to human 12q15.
For discussion of a possible role of MYF6 in a form of centronuclear myopathy, see 159991.0001.
In the mouse, Rhodes and Konieczny (1989) cloned cDNAs for a 'new' muscle regulatory factor gene and referred to it as Mrf4. Miner and Wold (1990) referred to the gene as herculin. The gene was designated MYF6 in human and Myf6 in the mouse.
Observations in Myf knockout mice indicate that MYF4 (159980) and MYF6 are involved in differentiation of myotubes (Yun and Wold, 1996).
Using an allelic series of 3 Myf5 (159990) mutants that differentially affect the expression of the genetically linked Mrf4 gene, Kassar-Duchossoy et al. (2004) demonstrated that skeletal muscle is present in Myf5:Myod (159970) double-null mice only when Mrf4 expression is not compromised. Kassar-Duchossoy et al. (2004) concluded that their finding contradicted the widely held view that myogenic identity is conferred solely by Myf5 and Myod, and identified Mrf4 as a determination gene. Kassar-Duchossoy et al. (2004) revised the epistatic relationship of the MRFs, in which both Myf5 and Mrf4 act upstream of Myod to direct embryonic multipotent cells into the myogenic lineage. Kassar-Duchossoy et al. (2004) found that Mrf4 can direct embryonic but not fetal skeletal muscle identity and differentiation in the absence of Myf5 and Myod. Myod is initially activated by Myf5 and Mrf4, and later through Pax3 (606597). Mrf4 drives myogenesis in the embryonic trunk and limbs, but not in embryonic head, or in the fetus.
This variant, formerly designated MYOPATHY, CENTRONUCLEAR, 3, has been reclassified based on a review of the gnomAD database by Hamosh (2019).
Kerst et al. (2000) found that haploinsufficiency for a 387G-T transversion in the MYF6 gene, resulting in an ala112-to-ser (A112S) mutation in a conserved residue of the protein, caused a mild form of centronuclear myopathy in a boy. The mutation was not found in 235 controls. In vitro functional expression studies showed that protein-protein interaction of mutant MYF6 was reduced, and DNA-binding potential and transactivation capacity were abolished, thus demonstrating MYF6 haploinsufficiency. The boy showed the first signs of myopathy at the age of 9 years when creatine kinase serum activities were elevated to 300-560 U/l. Three years later, creatine kinase activities were normal, but he complained of muscle cramps and weakness in his lower limbs during vigorous exercise. At that time, histologic muscle analysis showed myopathic changes with ring fibers and an increased percentage of central nuclei fibers. The boy's father carried the identical MYF6 mutation as well as an in-frame deletion of exons 45 to 47 in the dystrophin gene (DMD; 300377). This DMD mutation is usually associated with a mild to moderate course of Becker muscular dystrophy (300376), but the father suffered from a severe course of Becker muscular dystrophy, suggesting MYF6 as a modifier. Mutations, deletions, and rearrangements within the mitochondrial DNA were ruled out in the boy and his father. The father presented with cardiomyopathy, pectus carinatum, and severe muscular dystrophy and was wheelchair-bound by the age of 21 years. Muscle biopsy studies revealed massive fibrosis and discontinuous patchy immunostaining of dystrophin. This was said to be the first observation of a pathogenic defect of an MYF mutation in man.
The A112S variant was observed at low frequency in both the 1000 Genomes Project and the NHLBI Exome Variant Server databases; neither source provides information about specific clinical phenotypes of carriers (Scott, 2011).
Hamosh (2019) found that this variant was present in 327 of 282,470 alleles, with an allele frequency of 0.001158, in the gnomAD database (February 8, 2019).
Braun, T., Bober, E., Winter, B., Rosenthal, N., Arnold, H. H. Myf-6, a new member of the human gene family of myogenic determination factors: evidence for a gene cluster on chromosome 12. EMBO J. 9: 821-831, 1990. [PubMed: 2311584] [Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb08179.x]
Bureau, J. F., Bihl, F., Brahic, M., Le Paslier, D. The gene coding for interferon-gamma is linked to the D12S335 and D12S313 microsatellites and to the MDM2 gene. Genomics 28: 109-112, 1995. [PubMed: 7590734] [Full Text: https://doi.org/10.1006/geno.1995.1114]
Cupelli, L., Renault, B., Leblanc-Straceski, J., Banks, A., Ward, D., Kucherlapati, R. S., Krauter, K. Assignment of the human myogenic factors 5 and 6 (MYF5, MYF6) gene cluster to 12q21 by in situ hybridization and physical mapping of the locus between D12S350 and D12S106. Cytogenet. Cell Genet. 72: 250-251, 1996. [PubMed: 8978788] [Full Text: https://doi.org/10.1159/000134201]
Hamosh, A. Personal Communication. Baltimore, Md. 2/8/2019.
Kassar-Duchossoy, L., Gayraud-Morel, B., Gomes, D., Rocancourt, D., Buckingham, M., Shinin, V., Tajbakhsh, S. Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice. Nature 431: 466-471, 2004. [PubMed: 15386014] [Full Text: https://doi.org/10.1038/nature02876]
Kerst, B., Mennerich, D., Schuelke, M., Stoltenburg-Didinger, G., von Moers, A., Gossrau, R., van Landeghem, F. K. H., Speer, A., Braun, T., Hubner, C. Heterozygous myogenic factor 6 mutation associated with myopathy and severe course of Becker muscular dystrophy. Neuromusc. Disord. 10: 572-577, 2000. [PubMed: 11053684] [Full Text: https://doi.org/10.1016/s0960-8966(00)00150-4]
Miner, J. H., Wold, B. Herculin: a fourth member of the MyoD family of myogenic regulatory genes. Proc. Nat. Acad. Sci. 87: 1089-1093, 1990. [PubMed: 2300571] [Full Text: https://doi.org/10.1073/pnas.87.3.1089]
Rhodes, S. J., Konieczny, S. F. Identification of MRF4: a new member of the muscle regulatory factor gene family. Genes Dev. 3: 2050-2061, 1989. [PubMed: 2560751] [Full Text: https://doi.org/10.1101/gad.3.12b.2050]
Scott, A. F. Personal Communication. Baltimore, Md. 12/22/2011.
Yun, K., Wold, B. Skeletal muscle determination and differentiation: story of a core regulatory network and its context. Curr. Opin. Cell Biol. 8: 877-889, 1996. [PubMed: 8939680] [Full Text: https://doi.org/10.1016/s0955-0674(96)80091-3]