Alternative titles; symbols
HGNC Approved Gene Symbol: MYOD1
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:17,719,571-17,722,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | Congenital myopathy 17 | 618975 | Autosomal recessive | 3 |
The MYOD1 gene, which is expressed exclusively in skeletal muscle, encodes a protein that belongs to a family of transcription factors essential for myogenic differentiation and repair (summary by Shukla et al., 2019).
Davis et al. (1987) isolated the cDNAs for 3 distinct human myogenic factors, MYF3, MYF4 (159980), and MYF5 (159990), by weak cross-hybridization to the mouse MyoD1 probe. MYF3 proved to be the human homolog of mouse MyoD1.
Olson (1990) diagrammed a structural comparison of 4 mammalian myogenic regulatory factors: MYOD, myogenin (MYF4), MYF5, and MRF4 (159991). The region of homology is that involved in DNA binding for activation of myogenesis.
Weintraub et al. (1991) and Tapscott and Weintraub (1991) reviewed the role of the MyoD family in controlling specification of the muscle cell lineage. MyoD is expressed only in skeletal muscle and its precursors; in nonmuscle cells the gene is repressed by specific genes. MyoD activates its own transcription; this may stabilize commitment to myogenesis. The MyoD protein is a member of a large family of proteins related by sequence homology, the helix-loop-helix (HLH) proteins.
Sartorelli et al. (1999) showed that MYOD is directly acetylated by PCAF (602303) at evolutionarily conserved lysines (positions 99, 102, and 104). Acetylated MYOD displayed an increased affinity for its DNA target. Conservative substitutions of acetylated lysines with nonacetylatable arginines impaired the ability of MYOD to stimulate transcription and to induce conversion, indicating that acetylation of MYOD is functionally critical.
MYOD regulates skeletal muscle differentiation and is essential for repair of damaged tissue. NFKB (see 164011) is activated by the cytokine TNF (191160), a mediator of skeletal muscle wasting in cachexia. Guttridge et al. (2000) explored the role of NFKB in cytokine-induced muscle degeneration. In differentiating C2C12 myocytes, TNF-induced activation of NFKB inhibited smooth skeletal muscle differentiation by suppressing MYOD mRNA at the posttranscriptional level. In contrast, in differentiated myotubes, TNF plus interferon-gamma (IFNG; 147570) signaling was required for NFKB-dependent downregulation of MYOD and dysfunction of skeletal myofibers. MYOD mRNA was also downregulated by TNF and IFNG expression in mouse muscle in vivo. Guttridge et al. (2000) concluded that their data elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.
Mammalian SWI/SNF complexes are ATP-dependent chromatin remodeling enzymes that have been implicated in the regulation of gene expression, cell cycle control, and oncogenesis. MyoD is a muscle-specific regulator capable of inducing myogenesis in numerous cell types. To ascertain the requirement for chromatin remodeling enzymes in cellular differentiation processes, de la Serna et al. (2001) examined MyoD-mediated induction of muscle differentiation in fibroblasts expressing dominant-negative versions of the human brahma-related gene-1 (BRG1; 603254) or human brahma (BRM; 600014), the ATPase subunits of 2 distinct SWI/SNF enzymes. They found that induction of the myogenic phenotype was completely abrogated in the presence of the mutant enzymes. They further demonstrated that failure to induce muscle-specific gene expression correlated with inhibition of chromatin remodeling in the promoter region of an endogenous muscle-specific gene. The results demonstrated that SWI/SNF enzymes promote MyoD-mediated muscle differentiation and indicated that these enzymes function by altering chromatin structure in promoter regions of endogenous, differentiation-specific loci.
Bergstrom et al. (2002) used expression arrays and chromatin immunoprecipitation assays to demonstrate that myogenesis consists of discrete subprograms of gene expression regulated by MyoD. Approximately 5% of assayed genes altered expression in a specific temporal sequence, and more than 1% were regulated by MyoD without the synthesis of additional transcription factors. The authors showed that MyoD regulates genes expressed at different times during myogenesis and that promoter-specific regulation of MyoD binding is a major mechanism of patterning gene expression. In addition, p38 kinase (600289) activity was necessary for the expression of a restricted subset of genes regulated by MyoD, but not for MyoD binding.
Oculopharyngeal muscular dystrophy (OPMD; 164300) is caused by short expansions of the GCG trinucleotide repeat encoding the polyalanine tract of the poly(A)-binding protein 2 (PABP2; 602279). Kim et al. (2001) established stable mouse skeletal muscle C2 cell lines expressing human PABP2. The cells showed morphologically enhanced myotube formation accompanied by an increased transcription of myogenic factors MYOD and myogenin (MYF4). Using a yeast 2-hybrid system, ski-interacting protein (SKIP; 603055) was shown to bind to PABP2. Immunofluorescence studies showed that PABP2 colocalized with SKIP in nuclear speckles. Reporter assays showed that PABP2 cooperated with SKIP to synergistically activate E-box-mediated transcription through MYOD. Moreover, both PABP2 and SKIP were directly associated with MYOD to form a single complex. The authors suggested that PABP2 and SKIP directly control the expression of muscle-specific genes at the transcriptional level.
In response to genotoxic stress, cycling cells arrest at discrete boundaries in the cell cycle through the activation of checkpoints, thus allowing DNA repair and preventing propagation of chromosomal abnormalities to daughter cells. This surveillance mechanism is critical for the maintenance of genome integrity. In multicellular organisms, cell proliferation is often directed at generating specialized cell types through differentiation. Puri et al. (2002) hypothesized that genotoxic stress may trigger a differentiation checkpoint to prevent the formation of differentiated cells with genetic instability. They showed that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression was suppressed by DNA-damaging agents if applied before the induction of differentiation but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by the MYOD1 gene), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional ABL tyrosine kinase (ABL1; 189980), but occurs in cells deficient for p53 (TP53; 191170) or JUN (165160). These results supported the idea that genotoxic stress can regulate differentiation, and identified a new biologic function for the DNA damage-activated signaling network.
Mal and Harter (2003) presented data suggesting that in addition to its widely accepted role as an activator of differentiation-specific genes, MyoD also can perform as a transcriptional repressor in proliferating myoblasts while in partnership with a histone deacetylase. They showed by chromatin immunoprecipitation assays that MyoD and histone deacetylase-1 (HDAC1; 601241) both occupy the promoter of myogenin (159980) and that this gene is in a region of repressed chromatin.
By investigating MSX1 (142983) function in repression of myogenic gene expression, Lee et al. (2004) identified a physical interaction between MSX1 and H1B (142711). Lee et al. (2004) found that MSX1 and H1B bind to a key regulatory element of MYOD, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. Moreover, MSX1 and H1B cooperated to inhibit muscle differentiation in cell culture and in Xenopus animal caps. Lee et al. (2004) concluded that their findings defined a theretofore unknown function for linker histones in gene-specific transcriptional regulation.
Using chromatin immunoprecipitation studies, Rao et al. (2006) showed that MYOD1 and MYOG bound to regions upstream of several microRNAs, including miR1-1 (MIRN1; 609326) and miR133A1 (MIRN133A1; 610254), providing a basis for induction of these microRNAs during myogenesis.
By screening of hybrid cell DNA, Braun et al. (1989) assigned the MYF3 gene to human chromosome 11. This confirmed the localization by Tapscott et al. (1988), who suggested the same assignment by use of the heterologous mouse probe. The mouse MyoD1 gene is capable of inducing the myogenic phenotype in embryonic C3H mouse fibroblasts. It is of interest that a locus on human chromosome 11 has been associated with the development of embryonic tumors, including rhabdomyosarcoma (268210). Henry et al. (1989) mapped MYOD1, a marker for myogenic differentiation (Davis et al., 1987), to 11p15.4-p15.1 by Southern blot analysis of somatic cell hybrids containing different breakpoints in region 11p15. Scrable et al. (1990) determined that the MYOD1 gene is tightly linked to the structural gene for lactate dehydrogenase-A (150000) in band 11p15.4. They found that the corresponding locus in the mouse is close to the p ('pink-eyed dilution') and Ldh-1 loci on mouse chromosome 7. By in situ hybridization, Gessler et al. (1990) mapped the gene to 11p14, possibly 11p14.3. Furthermore, they showed by analysis of several somatic cell hybrids containing various derivatives with deletions or translocations that the MYF3 gene is not associated with the WAGR locus at chromosomal band 11p13 or with the loss of heterozygosity (LOH) region at 11p15.5 related to the Beckwith-Wiedemann syndrome.
In 3 affected sibs, born of consanguineous Caucasian parents, with congenital myopathy-17 (CMYP17; 618975), Watson et al. (2016) identified a homozygous nonsense mutation in the MYOD1 gene (S63X; 159970.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The sibs were severely affected, and all died in the first days of life. No functional studies of the variant were performed. Lopes et al. (2018) noted that the S63X mutation occurs in exon 1 of the MYOD1 gene and is predicted to result in nonsense-mediated mRNA decay with absence of the protein.
In an 8-year-old girl with CMYP17, Lopes et al. (2018) identified a homozygous nonsense mutation in the MYOD1 gene (E233X; 159970.0002). The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to escape nonsense-mediated mRNA decay.
In an 18-month-old girl, born of consanguineous Indian parents, with CMYP17, Shukla et al. (2019) identified a homozygous frameshift mutation in the MYOD1 gene (159970.0003). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project or gnomAD databases or in an in-house exome database of 538 Indians. Functional studies of the variant and studies of patient cells were not performed. A similarly affected older brother died at age 2 years, but DNA studies were not performed.
Mice carrying null mutations in either Myf5 (159990) 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 indicated 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 gene (159991), 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 3 affected sibs, born of consanguineous Caucasian parents, with congenital myopathy-17 (CMYP17; 618975), Watson et al. (2016) identified a homozygous c.188C-A transversion (c.188C-A, NM_002478.4) in the MYOD1 gene, resulting in a ser63-to-ter (S63X) substitution within the N-terminal basic domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing. The patients belonged to 2 sibships that shared the same mother. The unaffected mother and 1 of the fathers were heterozygous for the mutation; DNA from the other father was not available. (The sibs were also homozygous for a missense mutation in the OTOG gene (604487), for which the mother was heterozygous, but this variant was not considered causative.) The sibs were severely affected, and all died in the first days of life. No functional studies of the variant were performed.
Lopes et al. (2018) noted that the S63X mutation occurs in exon 1 of the MYOD1 gene and is predicted to result in nonsense-mediated mRNA decay with absence of the MYOD1 protein.
In an 8-year-old girl with congenital myopathy-17 (CMYP17; 618975), Lopes et al. (2018) identified a homozygous c.697G-T transversion in the MYOD1 gene, resulting in a glu233-to-ter (E233X) substitution. The mutation occurred within 13 bp of the exon2/exon3 junction, and was predicted to escape nonsense-mediated mRNA decay. The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In an 18-month-old girl, born of consanguineous Indian parents, with congenital myopathy-17 (CMYP17; 618975), Shukla et al. (2019) identified a homozygous 1-bp duplication (c.557dup, NM_002478.4) in exon 1 of the MYOD1 gene, resulting in a frameshift and premature termination (Arg188ProfsTer90). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. A similarly affected older brother died at age 2 years but no DNA studies were performed. The variant was not present in the 1000 Genomes Project or gnomAD databases or in an in-house exome database of 538 Indians. Functional studies of the variant and studies of patient cells were not performed.
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