HGNC Approved Gene Symbol: MYF5
Cytogenetic location: 12q21.31 Genomic coordinates (GRCh38): 12:80,716,912-80,719,671 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.31 | Ophthalmoplegia, external, with rib and vertebral anomalies | 618155 | Autosomal recessive | 3 |
To study the structure and function of a human factor involved in muscle development, Braun et al. (1989) isolated several cDNA clones from fetal human skeletal muscle by their weak cross-hybridization to a mouse MyoD1 (159970) probe. The complete clone MYF5, when expressed under the control of a viral promoter, converted mouse embryonic fibroblasts to myoblasts at high frequency. Braun et al. (1989) showed that the deduced protein sequence of MYF5 exhibits segmental conservation to mouse MyoD1, particularly in a domain that contains a region of basic amino acids and a strong homology to cellular and viral myc proteins. The highly conserved structure of 3 protein domains in mouse MyoD1 and human MYF5 and the same biologic activity in the myogenic conversion assay strongly suggested that the homology regions are involved in myogenic programming.
Braun et al. (1989) mapped the MYF5 gene to chromosome 12. 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.
Sequence analysis and the pattern of expression of MYF5 in human muscle showed that MYF5, although structurally related to MyoD1, constitutes a different protein that is nevertheless capable of inducing the myogenic phenotype in embryonic C3H mouse fibroblasts. In mice, the myogenic basic-helix-loop-helix genes are activated sequentially during the skeletal muscle developmental program. Myf5 mRNA was first detected in the 8-day somite and was markedly reduced after day 14 (Ott et al., 1991).
Seale et al. (2008) demonstrated by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express MYF5, a gene previously thought to be expressed only in the myogenic lineage. MYF5 mRNA was not detected in mature brown adipose tissue, indicating that MYF5 is transiently expressed at an early developmental stage.
In 5 affected individuals from 3 families with external ophthalmoplegia with rib and vertebral anomalies (EORVA; 618155), Di Gioia et al. (2018) identified homozygosity for mutations in the MYF5 gene: a missense mutation (R95C; 159990.0001) in 2 Yemeni sisters, and a 10-bp deletion in 3 affected members of 2 Turkish families (159990.0002). The mutations segregated with disease in the families and were not found in public variant databases.
Mice carrying null mutations in either Myf5 or MyoD have apparently normal skeletal muscle. Rudnicki et al. (1993) interbred mice carrying mutant Myf5 and MyoD genes and observed that mice lacking both genes were born alive but were immobile and died soon after birth. Histologic examination of these mice revealed complete absence of skeletal muscle. Immunohistochemical analysis indicated an absence of desmin-expressing myoblast-like cells. These observations suggested that either Myf5 or MyoD is required for the determination of skeletal myoblasts, their propagation, or both during embryonic development, and indicate that these factors play, at least in part, functionally redundant roles in myogenesis.
Using an allelic series of Myf5 mutants that differentially affect the expression of the genetically linked Mrf4 (159991) gene, Kassar-Duchossoy et al. (2004) demonstrated that skeletal muscle is present in Myf5:Myod 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 the head or the fetus.
In 2 Yemeni sisters (family BX) who had external ophthalmoplegia with rib and vertebral anomalies (EORVA; 618155), originally reported by Traboulsi et al. (2000), Di Gioia et al. (2018) identified homozygosity for a c.283C-T transition (c.283C-T, NM_005593.2) in exon 1 of the MYF5 gene, resulting in an arg95-to-cys (R95C) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in the 1000 Genomes Project, gnomAD, or ExAC databases. Functional analysis in transfected C3H10T1/2 cells revealed minimal activation with the R95C mutant compared to wildtype MYF5. Fractionation of the transfected cells demonstrated the presence of signal in the nuclear fraction with wildtype but not mutant MYF5. Quantitative analysis showed that both proteins localized to the nucleus, but wildtype localized to the nucleus more often (approximately 20% of nuclei) than the R95C mutant (fewer than 10% of nuclei). The authors concluded that the R95C mutation impairs both nuclear localization and transcriptional activity of MYF5.
In 3 affected individuals from 2 Turkish families (ALO and CHO) with external ophthalmoplegia with rib and vertebral anomalies (EORVA; 618155), Di Gioia et al. (2018) identified homozygosity for a 10-bp deletion (c.23_32delAGTTCTCACC, NM_005593.2) in exon 1 of the MYF5 gene, causing a frameshift predicted to result in a premature termination codon (Gln8LeufsTer86). The mutation segregated with disease in both families and was not found in the 1000 Genomes Project, gnomAD, or ExAC databases.
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]
Braun, T., Buschhausen-Denker, G., Bober, E., Tannich, E., Arnold, H. H. A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts. EMBO J. 8: 701-709, 1989. [PubMed: 2721498] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb03429.x]
Braun, T., Grzeschik, K.-H., Bober, E., Arnold, H.-H. The MYF genes, a group of human muscle determining factors, are localized on different human chromosomes.(Abstract) Cytogenet. Cell Genet. 51: 969, 1989.
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]
Di Gioia, S. A., Shaaban, S., Tuysuz, B., Elcioglu, N. H., Chan, W.-M., Robson, C. D., Ecklund, K., Gilette, N. M., Hamzaoglu, A., Tayfun, G. A., Traboulsi, E. I., Engle, E. C. Recessive MYF5 mutations cause external ophthalmoplegia, rib, and vertebral anomalies. Am. J. Hum. Genet. 103: 115-124, 2018. [PubMed: 29887215] [Full Text: https://doi.org/10.1016/j.ajhg.2018.05.003]
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]
Ott, M.-O., Bober, E., Lyons, G., Arnold, H.-H., Buckingham, M. Early expression of the myogenic regulatory gene, Myf-5, in precursor cells of skeletal muscle in the mouse embryo. Development 111: 1097-1107, 1991. [PubMed: 1652425] [Full Text: https://doi.org/10.1242/dev.111.4.1097]
Rudnicki, M. A., Schnegelsberg, P. N. J., Stead, R. H., Braun, T., Arnold, H.-H., Jaenisch, R. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75: 1351-1359, 1993. [PubMed: 8269513] [Full Text: https://doi.org/10.1016/0092-8674(93)90621-v]
Seale, P., Bjork, B., Yang, W., Kajimura, S., Chin, S., Kuang, S., Scime, A., Devarakonda, S., Conroe, H. M., Erdjument-Bromage, H., Tempst, P., Rudnicki, M. A., Beier, D. R., Spiegelman, B. M. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454: 961-967, 2008. [PubMed: 18719582] [Full Text: https://doi.org/10.1038/nature07182]
Traboulsi, E. I., Lee, B. A., Mousawi, A., Khamis, A. R., Engle, E. C. Evidence of genetic heterogeneity in autosomal recessive congenital fibrosis of the extraocular muscles. Am. J. Ophthal. 129: 658-662, 2000. [PubMed: 10844060] [Full Text: https://doi.org/10.1016/s0002-9394(99)00467-5]