Alternative titles; symbols
HGNC Approved Gene Symbol: MYOCD
Cytogenetic location: 17p12 Genomic coordinates (GRCh38) : 17:12,665,890-12,768,949 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p12 | Megabladder, congenital | 618719 | Autosomal dominant | 3 |
Myocardin is a smooth and cardiac muscle-specific transcriptional coactivator of serum response factor. When expressed ectopically in nonmuscle cells, myocardin can induce smooth muscle differentiation by its association with serum response factor (SRF; 600589) (Wang et al., 2001; Wang et al., 2003).
Using a bioinformatics-based screen for cardiac-specific genes, Wang et al. (2001) identified a highly potent murine transcription factor, myocardin, that is expressed in cardiac and smooth muscle cells. They identified a genomic sequence that represents the human homolog of mouse myocardin. The 807-amino acid mouse myocardin protein belongs to the SAP (SAFA (602869)/SAFB (602895), acinus (604562), and PIAS (see 603566)) domain family of nuclear proteins, which regulate diverse aspects of chromatin remodeling and transcription. Myocardin activates cardiac muscle promoters by associating with SRF. Expression of a dominant-negative mutant of myocardin in Xenopus embryos interfered with myocardial cell differentiation. The authors concluded that myocardin is the founding member of a class of muscle transcription factors and provides a mechanism whereby SRF can convey myogenic activity to cardiac muscle genes.
By RT-PCR analysis, Yoshida et al. (2003) determined that mouse myocardin is expressed in many tissues containing smooth muscle, including aorta, bladder, stomach, intestine, and colon, as well as in the heart. Myocardin was not expressed in mouse brain, liver, and skeletal muscle.
By Northern blot analysis, Du et al. (2003) detected expression of human and murine myocardin in numerous tissues containing vascular and visceral smooth muscle cells (SMCs), and the levels were at least equivalent to those observed in specific heart regions. In situ hybridization of developing mouse embryos indicated that myocardin was expressed abundantly in a precise, developmentally regulated pattern in SMCs.
Creemers et al. (2006) identified 2 splice variants of mouse myocardin with different 5-prime ends. The variant encoding the full-length 935-amino acid protein initiates translation from an ATG codon in exon 1. The other variant, which includes exon 2a between exons 2 and 3, encodes an N-terminally truncated 856-amino acid protein that is translated from an ATG codon within exon 4. The truncated protein contains domains required for SRF interaction and transcriptional activation, but it lacks the N-terminal MEF2 (see 600662)-interacting sequence. RT-PCR analysis showed that the myocardin transcript lacking exon 2a was expressed in heart, whereas the transcript containing exon 2a was expressed in smooth muscle.
Using RT-PCR analysis, Imamura et al. (2010) detected Myocd mRNA expression in rat heart and SMC-rich tissues, with highest expression in heart, followed by aorta and bladder. Myocd mRNA was not expressed in SMC-poor tissues in rat. Conventional and quantitative RT-PCR revealed conserved expression of 4 alternatively spliced MYOCD variants in mouse, rat, and human tissues: 2 cardiac-type MYOCD variants and 2 SMC-type MYOCD variants.
Creemers et al. (2006) determined that the mouse myocardin gene contains 14 exons. An additional exon, exon 2a, is spliced into smooth muscle myocardin transcripts.
Imamura et al. (2010) stated that the MYOCD gene contains at least 15 exons, including the alternatively spliced exons 2a and 10a.
Wang et al. (2001) identified a genomic sequence (GenBank AC005358) mapping to chromosome 17 that represents human myocardin.
Virtually all smooth muscle genes contain 2 or more essential binding sites for SRF in their control regions. Because SRF is expressed in a wide range of cell types, it alone cannot account for smooth muscle-specific gene expression. Wang et al. (2003) showed that myocardin can activate smooth muscle gene expression in a variety of nonmuscle cell types via its association with SRF. They found that homodimerization of myocardin is required for maximal transcriptional activity and provides a mechanism for cooperative activation of smooth muscle genes by SRF-myocardin complexes bound to different SRF binding sites. These findings identified myocardin as a master regulator of smooth muscle gene expression and explained how SRF conveys smooth muscle specificity to its target genes.
Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues. SRF activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin, and ternary complex factors (TCFs) of the ETS-domain family, respectively. Wang et al. (2004) showed that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by ELK1 (311040), a TCF that acts as a myogenic repressor. The opposing influences of myocardin and ELK1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directed ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. Wang et al. (2004) concluded that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.
Du et al. (2003) found that forced expression of myocardin in COS-7 cells caused transactivation of multiple SMC-specific transcriptional regulatory elements. Myocardin-induced transactivation was not observed in Srf -/- mouse embryonic stem cells, but it could be rescued by forced expression of Srf or the Srf DNA-binding domain. Expression of a dominant-negative myocardin mutant protein or small interfering RNA-induced myocardin knockdown significantly reduced Sm22-alpha (TAGLN; 600818) promoter activity in SMCs. Conversely, forced expression of myocardin activated expression of Sm22-alpha, smooth muscle alpha-actin (ACTC; 102540), and calponin-H1 (CNN1; 600806) in undifferentiated mouse embryonic stem cells. Du et al. (2003) concluded that myocardin plays an important role in the SRF-dependent transcriptional program that regulates SMC development and differentiation.
Liu et al. (2005) found that Foxo4 (MLLT7; 300033) repressed SMC differentiation in several rodent SMC lines by interacting with and inhibiting the activity of myocardin. PI3K (see 601232)/Akt (see 164730) signaling promoted SMC differentiation, at least in part, by stimulating nuclear export of Foxo4 and thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by small interfering RNA enhanced myocardin activity and SMC differentiation. Liu et al. (2005) concluded that signal-dependent interaction of FOXO4 with myocardin couples extracellular signals with the transcriptional program of SMC differentiation.
By mutation analysis, Creemers et al. (2006) showed that the N terminus of the mouse full-length cardiac myocardin isoform mediated Mef2-dependent transcription from CArG boxes. The Mef2-interacting region is absent in the N-terminally truncated smooth muscle myocardin isoform. Both isoforms activated SRF-dependent reporter genes; stimulation of SRF activity required the basic and glutamine-rich regions and the C-terminal transcriptional activation domain.
Li et al. (2007) found that SRC3 (NCOA3; 601937) is a coactivator for myocardin. In vitro and in vivo studies showed that the N terminus of SRC3 binds the C-terminal activation domain of myocardin and enhances myocardin-mediated transcriptional activation of vascular smooth muscle cell-specific genes. This interaction identified a site of convergence for nuclear hormone receptor-mediated and smooth muscle cell-specific gene regulation, suggesting a possible mechanism for the vascular protective effects of estrogen on vascular injury.
Using lineage tracing studies in mice, Long et al. (2007) showed that Myocd was expressed transiently in skeletal muscle progenitor cells of the somite and that a majority of skeletal muscle was derived from Myocd-expressing cell lineages. However, rather than activating skeletal muscle-specific genes, Myocd functioned as a transcriptional repressor of Myog (159980), thus inhibiting skeletal muscle differentiation while activating smooth muscle cell-specific genes. The repressor function of Myocd was complex, involving Hdac5 (605315) silencing of the Myog promoter and the interaction of Myocd with Myod (159970), which undermined Myod DNA binding and transcriptional activity. Long et al. (2007) concluded that MYOCD acts as a bifunctional molecular switch for smooth versus skeletal muscle phenotypes.
In vascular smooth muscle cells (VSMC) isolated from AD (104300) patients with CAA (605714), Bell et al. (2009) found an association between beta-amyloid (104760) deposition and increased expression of SRF and myocardin compared to controls. Further studies indicated the MYOCD upregulated SRF and generated a beta-amyloid nonclearing phenotype through transactivation of SREBP2 (600481), which downregulates LRP1 (107770), a key beta-amyloid clearance receptor. SRF silencing led to increased beta-amyloid clearance. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. Bell et al. (2009) suggested that SRF and MYOCD function as a transcriptional switch, controlling beta-amyloid cerebrovascular clearance and progression of AD.
Megabladder, Congenital
In 7 affected males from 3 families with congenital megabladder (MGBL; 618719), Houweling et al. (2019) identified heterozygous mutations in the MYOCD gene (606127.0001-606127.0003). Female carriers were unaffected. The authors also reported a woman (family A) with a history of antenatal megabladder who underwent cardiac evaluation at age 32 years and was found to have noncompaction cardiomyopathy, dilation of the aortic root, and multiple congenital heart defects. In that family, a terminated male fetus had been diagnosed prenatally with megabladder and ventricular septal defect. Both sibs were compound heterozygous for a missense (E530G) and a frameshift (c.684dupC; Ser229GlnfsTer17) mutation in the MYOCD gene; their unaffected mother and father were heterozygous for the missense mutation and frameshift mutation, respectively. Autopsy of the male fetus showed 'prune belly' syndrome, and histology revealed disorganized smooth muscle (SM) bundles in the bladder and glomerular cysts in the kidneys. The hindgut lacked the longitudinal SM layer that should have been present, but the small intestine had 2 normal SM layers and pulmonary artery SM appeared normal.
Associations Pending Confirmation
Kontaraki et al. (2008) studied polymorphisms in the MYOCD gene in 36 Cretan patients with hypertrophic cardiomyopathy (see CMH, 192600) and 48 age- and sex-matched controls and identified 2 polymorphisms in the promoter region, -435T/C (rs758187) and -629A/T, that were in near complete linkage disequilibrium and were associated with reduced left ventricular wall thickness and left ventricular mass in CMH patients. Carriers of the -435C;-629T promoter allele had significantly lower myocardin mRNA levels in peripheral blood than wildtype homozygotes. Kontaraki et al. (2008) concluded that myocardin promoter variation might be a genetic factor contributing to interindividual differences in the development of cardiac hypertrophy.
Alazami et al. (2015) performed whole-exome sequencing in 143 consanguineous families with a multiplex neurogenetic diagnosis and no candidate genes identified by autozygosity mapping. They studied a consanguineous family (13DG1549) in which a 6-year-old girl exhibited speech delay in early childhood and walked at 16 months, but thereafter regressed in gross motor development and language. At age 5 she developed persistent seizures following a flu-like febrile illness, and at age 5.5 years, she was unable to walk unsupported and could not form a 2-word phrase. Brain MRI showed bilateral multiple small hyperintense regions in the white matter of the centrum ovale, with early changes of demyelination. She had a sister with speech delay. The authors detected homozygosity for a missense variant in the MYOCD gene (c.1252A-G, I418V, NM_001146312) that segregated in the family. No functional studies were reported.
Li et al. (2003) reported that most mouse embryos homozygous for a myocardin loss-of-function mutation died by embryonic day 10.5 and showed no evidence of vascular smooth muscle cell differentiation. Myocardin is the only transcription factor known to be necessary and sufficient for vascular smooth muscle cell differentiation.
Huang et al. (2008) selectively ablated the Myocd gene in mouse neural crest. Mutant mice were born at the expected mendelian ratio, but they died prior to postnatal day 3 from patent ductus arteriosus. Mutant pups exhibited a defect in expression of Myocd-regulated genes encoding SMC contractile proteins. Huang et al. (2008) concluded that MYOCD plays a critical role in differentiation of neural crest-derived SMCs populating the great arteries, as well as in maintenance of the contractile SMC phenotype.
Huang et al. (2009) found that mice with cardiac-restricted deletion of Myocd developed dilated cardiomyopathy with disrupted cardiomyocyte structural organization and did not survive beyond 1 year. Myocd acted in a cell-autonomous fashion and was required for maintenance of cardiac contractile function and structural organization of cardiomyocytes during postnatal development. Cell-autonomous loss of Myocd triggered apoptosis, resulting in loss of cardiac myocytes.
Houweling et al. (2019) studied mice that were compound heterozygous for a deletion of critical residues within the leucine zipper of the Myocd gene and a null allele. The mutant mice developed grossly dilated bladders with little or no smooth muscle in the bladder wall. In mutant bladders, transcript levels of several Myocd target genes were blunted compared to wildtype. The authors generated mice that were compound heterozygous for a translocation on chromosome 11 involving a putative upstream Myocd enhancer and a null Myocd allele (designated 'mgb/-') and observed megabladders in the mutant mice. The mgb/- mutants also had patent ductus arteriosus, which was not seen in Myocd +/- mice with only 1 mutated allele. The authors noted that although the mgb/- mutants had severely reduced levels of Myocd target genes in their bladders, their aortas and hearts showed levels of target transcripts similar to those of controls. Analysis of various Myocd mutants showed that a 70 to 80% reduction in Myocd mRNA in the bladder is sufficient to produce megabladder in mice. The authors concluded that MYOCD plays a unique role in proper development of the bladder wall.
In 3 affected brothers from a large 4-generation family (family B) segregating male-limited congenital megabladder (MGBL; 618719), Houweling et al. (2019) identified heterozygosity for a c.343C-T transition in the MYOCD gene, resulting in an arg115-to-ter (R115X) substitution within an RPEL domain. The mutation was also present in their unaffected mother, maternal grandmother, and maternal great-aunt, as well as a healthy sister. The maternal grandmother reported a male stillbirth of unknown cause in the third trimester, and she had 4 brothers who died antenatally due to megabladder. Western blot analysis showed that the R115X mutation produced a truncated protein. Analysis of transiently transfected mouse fibroblasts showed no activation of a Tagln (600818)-luciferase reporter by the R115X mutant, in contrast to wildtype MYOCD, and quantitative PCR demonstrated a significantly blunted response of smooth muscle transcripts (Tagln; Myh11, 160745; Cnn1, 600806; Mylk, 600922) with the mutant compared to wildtype MYOCD.
In 3 affected males from a 4-generation family (family D) segregating male-limited congenital megabladder (MGBL; 618719), Houweling et al. (2019) identified heterozygosity for a 1-bp deletion, designated c.1053_1054del, resulting in a frameshift and a premature termination codon (Asn351LysTer19). The mutation was present in an unaffected sister as well as in the unaffected father of 1 of the patients, suggesting incomplete penetrance.
In a male fetus (family C) with congenital megabladder (MGBL; 618719), Houweling et al. (2019) identified heterozygosity for a de novo 420-kb deletion (chr17.12,172,568-12,609,597, GRCh37) encompassing exons 1 and 2 of the MYOCD gene.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Bell, R. D., Deane, R., Chow, N., Long, X., Sagare, A., Singh, I., Streb, J. W., Guo, H., Rubio, A., Van Nostrand, W., Miano, J. M., Zlokovic, B. V. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nature Cell Biol. 11: 143-153, 2009. [PubMed: 19098903] [Full Text: https://doi.org/10.1038/ncb1819]
Creemers, E. E., Sutherland, L. B., Oh, J., Barbosa, A. C., Olson, E. N. Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR. Molec. Cell 23: 83-96, 2006. [PubMed: 16818234] [Full Text: https://doi.org/10.1016/j.molcel.2006.05.026]
Du, K. L., Ip, H. S., Li, J., Chen, M., Dandre, F., Yu, W., Lu, M. M., Owens, G. K., Parmacek, M. S. Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Molec. Cell. Biol. 23: 2425-2437, 2003. [PubMed: 12640126] [Full Text: https://doi.org/10.1128/MCB.23.7.2425-2437.2003]
Houweling, A. C., Beaman, G. M., Postma, A. V., Gainous, T. B., Lichtenbelt, K. D., Brancati, F., Lopes, F. M., van der Made, I., Polstra, A. M., Robinson, M. L., Wright, K. D., Ellingford, J. M., and 13 others. Loss-of-function variants in myocardin cause congenital megabladder in humans and mice. J. Clin. Invest. 129: 5374-5380, 2019. [PubMed: 31513549] [Full Text: https://doi.org/10.1172/JCI128545]
Huang, J., Cheng, L., Li, J., Chen, M., Zhou, D., Lu, M. M., Proweller, A., Epstein, J. A., Parmacek, M. S. Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice. J. Clin. Invest. 118: 515-525, 2008. [PubMed: 18188448] [Full Text: https://doi.org/10.1172/JCI33304]
Huang, J., Lu, M. M., Cheng, L., Yuan, L.-J., Zhu, X., Stout, A. L., Chen, M., Li, J., Parmacek, M. S. Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc. Nat. Acad. Sci. 106: 18734-18739, 2009. [PubMed: 19850880] [Full Text: https://doi.org/10.1073/pnas.0910749106]
Imamura, M., Long, X., Nanda, V., Miano, J. M. Expression and functional activity of four myocardin isoforms. Gene 464: 1-10, 2010. [PubMed: 20385216] [Full Text: https://doi.org/10.1016/j.gene.2010.03.012]
Kontaraki, J. E., Parthenakis, F. I., Patrianakos, A. P., Karalis, I. K., Vardas, P. E. Myocardin gene regulatory variants as surrogate markers of cardiac hypertrophy--study in a genetically homogeneous population. Clin. Genet. 73: 71-78, 2008. [PubMed: 18028454] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00932.x]
Li, H. J., Haque, Z., Lu, Q., Li, L., Karas, R., Mendelsohn, M. Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation. Proc. Nat. Acad. Sci. 104: 4065-4070, 2007. [PubMed: 17360478] [Full Text: https://doi.org/10.1073/pnas.0611639104]
Li, S., Wang, D.-Z., Wang, Z., Richardson, J. A., Olson, E. N. The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proc. Nat. Acad. Sci. 100: 9366-9370, 2003. [PubMed: 12867591] [Full Text: https://doi.org/10.1073/pnas.1233635100]
Liu, Z.-P., Wang, Z., Yanagisawa, H., Olson, E. N. Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev. Cell 9: 261-270, 2005. [PubMed: 16054032] [Full Text: https://doi.org/10.1016/j.devcel.2005.05.017]
Long, X., Creemers, E. E., Wang, D.-Z., Olson, E. N., Miano, J. M. Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation. Proc. Nat. Acad. Sci. 104: 16570-16575, 2007. [PubMed: 17940050] [Full Text: https://doi.org/10.1073/pnas.0708253104]
Wang, D.-Z., Chang, P. S., Wang, Z., Sutherland, L., Richardson, J. A., Small, E., Krieg, P. A., Olson, E. N. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105: 851-862, 2001. [PubMed: 11439182] [Full Text: https://doi.org/10.1016/s0092-8674(01)00404-4]
Wang, Z., Wang, D.-Z., Hockemeyer, D., McAnally, J., Nordheim, A., Olson, E. N. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428: 185-189, 2004. [PubMed: 15014501] [Full Text: https://doi.org/10.1038/nature02382]
Wang, Z., Wang, D.-Z., Pipes, G. C. T., Olson, E. N. Myocardin is a master regulator of smooth muscle gene expression. Proc. Nat. Acad. Sci. 100: 7129-7134, 2003. [PubMed: 12756293] [Full Text: https://doi.org/10.1073/pnas.1232341100]
Yoshida, T., Sinha, S., Dandre, F., Wamhoff, B. R., Hoofnagle, M. H., Kremer, B. E., Wang, D.-Z., Olson, E. N., Owens, G. K. Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ. Res. 92: 856-864, 2003. [PubMed: 12663482] [Full Text: https://doi.org/10.1161/01.RES.0000068405.49081.09]