MEF2A

Summary

MEF2A (myocyte enhancer factor 2A, HGNC:6993) is a protein-coding gene on chromosome 15q26.3, encoding Myocyte-specific enhancer factor 2A (Q02078). Transcriptional activator which binds specifically to the MEF2 element, 5’-YTAATTAR-3’, found in numerous muscle-specific genes.

The protein encoded by this gene is a DNA-binding transcription factor that activates many muscle-specific, growth factor-induced, and stress-induced genes. The encoded protein can act as a homodimer or as a heterodimer and is involved in several cellular processes, including muscle development, neuronal differentiation, cell growth control, and apoptosis. Defects in this gene could be a cause of autosomal dominant coronary artery disease 1 with myocardial infarction (ADCAD1). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4205 — RefSeq curated summary.

At a glance

• Gene–disease (curated): coronary artery disease, autosomal dominant, 1 (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 78 total — 4 pathogenic
• Phenotypes (HPO): 9
• Transcription factor: yes — 125 downstream targets (CollecTRI)
• MANE Select transcript: NM_001319206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6993
Approved symbol	MEF2A
Name	myocyte enhancer factor 2A
Location	15q26.3
Locus type	gene with protein product
Status	Approved
Aliases	RSRFC4, RSRFC9
Ensembl gene	ENSG00000068305
Ensembl biotype	protein_coding
OMIM	600660
Entrez	4205

Gene structure

Transcript identifiers

Ensembl transcripts: 115 — 111 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000338042, ENST00000354410, ENST00000449277, ENST00000557785, ENST00000557942, ENST00000558049, ENST00000558812, ENST00000558856, ENST00000558983, ENST00000559036, ENST00000559903, ENST00000560493, ENST00000561125, ENST00000685785, ENST00000686611, ENST00000690055, ENST00000691492, ENST00000705985, ENST00000889124, ENST00000889125, ENST00000889126, ENST00000889127, ENST00000889128, ENST00000889129, ENST00000889130, ENST00000889131, ENST00000889132, ENST00000889133, ENST00000889134, ENST00000889135, ENST00000889136, ENST00000889137, ENST00000889138, ENST00000889139, ENST00000889140, ENST00000889141, ENST00000889142, ENST00000889143, ENST00000889144, ENST00000889145, ENST00000889146, ENST00000889147, ENST00000889148, ENST00000889149, ENST00000889150, ENST00000889151, ENST00000889152, ENST00000889153, ENST00000889154, ENST00000889155, ENST00000889156, ENST00000889157, ENST00000889158, ENST00000889159, ENST00000889160, ENST00000889161, ENST00000889162, ENST00000889163, ENST00000928332, ENST00000928333, ENST00000928334, ENST00000928335, ENST00000946975, ENST00000946976, ENST00000946977, ENST00000946978, ENST00000946979, ENST00000946980, ENST00000946981, ENST00000946982, ENST00000946983, ENST00000946984, ENST00000946985, ENST00000946986, ENST00000946987, ENST00000946988, ENST00000946989, ENST00000946990, ENST00000946991, ENST00000946992, ENST00000946993, ENST00000946994, ENST00000946995, ENST00000946996, ENST00000946997, ENST00000946998, ENST00000946999, ENST00000947000, ENST00000947001, ENST00000947002, ENST00000947003, ENST00000947004, ENST00000947005, ENST00000947006, ENST00000947007, ENST00000947008, ENST00000947009, ENST00000947010, ENST00000947011, ENST00000947012, ENST00000947013, ENST00000947014, ENST00000947015, ENST00000947016, ENST00000947017, ENST00000947018, ENST00000947019, ENST00000947020, ENST00000947021, ENST00000947022, ENST00000947023, ENST00000947024, ENST00000947025, ENST00000947026, ENST00000947027

RefSeq mRNA: 62 — MANE Select: NM_001319206 NM_001130926, NM_001130927, NM_001130928, NM_001171894, NM_001319206, NM_001352614, NM_001352615, NM_001352616, NM_001352617, NM_001352618, NM_001365201, NM_001365202, NM_001365203, NM_001365204, NM_001365205, NM_001365206, NM_001365207, NM_001365208, NM_001365209, NM_001365210, NM_001365211, NM_001393558, NM_001393559, NM_001393560, NM_001393561, NM_001400028, NM_001400029, NM_001400030, NM_001400031, NM_001400032, NM_001400033, NM_001400034, NM_001400035, NM_001400036, NM_001400037, NM_001400038, NM_001400039, NM_001400040, NM_001400049, NM_001400050, NM_001400051, NM_001400052, NM_001400053, NM_001400054, NM_001400055, NM_001400056, NM_001400057, NM_001400058, NM_001400059, NM_001400060, NM_001400061, NM_001400062, NM_001400063, NM_001400064, NM_001400065, NM_001400066, NM_001400067, NM_001400068, NM_001400069, NM_001400070, NM_001400071, NM_005587

CCDS: CCDS45362, CCDS45363, CCDS53978, CCDS58401, CCDS81920, CCDS92067, CCDS92068

Canonical transcript exons

ENST00000557942 — 12 exons

Exon	Start	End
ENSE00000900772	99675399	99675458
ENSE00000900773	99674393	99674612
ENSE00001315420	99598430	99598511
ENSE00001376615	99671323	99671454
ENSE00001403949	99690241	99690428
ENSE00001433734	99706729	99706855
ENSE00001621136	99703362	99703385
ENSE00002544094	99712390	99716488
ENSE00003529738	99632978	99633173
ENSE00003603003	99710634	99710760
ENSE00003625799	99645561	99645764
ENSE00003938717	99565984	99566104

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.5473 / max 615.2585, expressed in 1810 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148893	33.0867	1799
148894	2.2800	955
148890	1.9337	1182
148896	1.7435	715
148891	0.5311	281
148895	0.5000	271
148892	0.3496	140
148897	0.1226	40

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.61	gold quality
myocardium	UBERON:0002349	97.73	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.62	gold quality
heart right ventricle	UBERON:0002080	97.38	gold quality
left ventricle myocardium	UBERON:0006566	97.26	gold quality
biceps brachii	UBERON:0001507	96.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.81	gold quality
middle temporal gyrus	UBERON:0002771	96.39	gold quality
upper leg skin	UBERON:0004262	96.39	gold quality
tibia	UBERON:0000979	96.25	gold quality
deltoid	UBERON:0001476	96.23	gold quality
gluteal muscle	UBERON:0002000	96.21	gold quality
skin of hip	UBERON:0001554	96.05	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.92	gold quality
vastus lateralis	UBERON:0001379	95.82	gold quality
tibialis anterior	UBERON:0001385	95.73	gold quality
triceps brachii	UBERON:0001509	95.58	gold quality
tendon	UBERON:0000043	95.45	gold quality
postcentral gyrus	UBERON:0002581	95.45	gold quality
quadriceps femoris	UBERON:0001377	95.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.35	gold quality
skeletal muscle tissue	UBERON:0001134	95.34	gold quality
cauda epididymis	UBERON:0004360	95.30	gold quality
muscle tissue	UBERON:0002385	95.15	gold quality
blood vessel layer	UBERON:0004797	95.14	gold quality
ascending aorta	UBERON:0001496	95.11	gold quality
thoracic aorta	UBERON:0001515	95.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.05	gold quality
cardiac atrium	UBERON:0002081	94.85	gold quality
descending thoracic aorta	UBERON:0002345	94.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	50.24
E-HCAD-25	yes	23.16
E-ANND-3	yes	8.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

125 targets.

Target	Regulation
ABRA
ACTA2
ACTG2	Activation
ADAM2
ADK
AGTR1
AKT1
AKT2
ALDOA	Unknown
ART1
ASPH
ATF3
ATP2A2	Activation
ATP6V1B2
ATXN1
AVP
BARX2
BCO1	Unknown
BDNF
BMP2	Unknown
BPIFA4P
CABIN1
CALM1
CAMK2A
CAMK4
CD14
CD44
CDK5
CKM	Activation
CLCA1

JASPAR motifs

Motif	Name	Family
MA0052.1	MEF2A	Regulators of differentiation
MA0052.2	MEF2A	Regulators of differentiation
MA0052.3	MEF2A	Regulators of differentiation
MA0052.4	MEF2A	Regulators of differentiation
MA0052.5	MEF2A	Regulators of differentiation

JASPAR matrix evidence (PMIDs): PMID:1748287, PMID:25217591

Upstream regulators (CollecTRI, top): ATF6, HDAC4, HDAC5, HDAC7, HDAC9, KLF2, MEF2A, MEF2C, MEF2D, MYCN, MYF5, MYF6, MYOD1, MYOG, NKX2-6, NR4A1

miRNA regulators (miRDB)

287 targeting MEF2A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Literature-anchored findings (GeneRIF, showing 40)

• The C-terminal region in MEF2A contains signals that are necessary to localize the histone deacetylase 4/MEF2 complex to the nucleus. (PMID:11792813)
• identification of two aspects of MEF2 regulation, a highly conserved phosphoacceptor site and an indirect pathway of regulation by p38 MAPK (PMID:12586839)
• MEF2a binding to HDAC5 is inhibited by HDAC5 when bound to Ca(2+)/calmodulin (PMID:12626519)
• GEF and MEF2A have roles in regulating the GLUT4 promoter (PMID:14630949)
• an autosomal dominant form of coronary artery disease/myocardial infarction (adCAD1) that is caused by the deletion of seven amino acids in transcription factor MEF2A is described (PMID:14645853)
• Activation of MEF2 in skeletal muscle is regulated via parallel intracellular signaling pathways in response to insulin, cellular stress, or activation of AMPK. (PMID:14960415)
• MEF2A is a candidate for chronic diaphragmatic hernia; it maps to chromosome 15. (PMID:15057983)
• myogenin and myocyte enhancer factor-2 expression are triggered by membrane hyperpolarization during human myoblast differentiation (PMID:15084602)
• promoter- and cell-specific functional interaction between PITX2 and MEF2A (PMID:15466416)
• Myocyte enhancer factor 2 activates P2 promoter of the AbetaH-J-J locus. (PMID:15798210)
• One disease-causing gene for CAD and MI has been identified as MEF2A, which is located on chromosome 15q26.3 and encodes a transcriptional factor with a high level of expression in coronary endothelium. (PMID:15811259)
• A conserved pattern of alternative splicing in vertebrate MEF2 (myocyte enhancer factor 2) genes generates an acidic activation domain in MEF2 proteins selectively in tissues where MEF2 target genes are highly expressed. (MEF2) (PMID:15834131)
• Results suggest that MEF2A mutations are not a common cause of coronary artery disease (CAD) in white people and argue strongly against a role for the MEF2A 21-bp deletion in autosomal dominant CAD. (PMID:15841183)
• The MEF2A mutations may account for up to 1.93% of the disease population; thus, genetic testing based on mutational analysis of MEF2A may soon be available for many coronary artery disease/myocardial infarction patients. (PMID:15861005)
• The genetic risk factor for myocardial infarction could be the result of a reduced transcriptional activity on MEF2A with 279Leu. (PMID:15958500)
• MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy (PMID:16043483)
• Binding of this protein to DNA resulted in significant changes of its diffusion. (PMID:16314281)
• data show a dosage-dependent cardiomyopathic phenotype and a progressive reduction in ventricular performance associated with MEF2A or MEF2C overexpression (PMID:16469744)
• Study demonstrates that human intestinal cell BCMO1 expression is dependent on the functional cooperation between peroxisome proliferator-activated receptor-gamma and myocyte enhancer factor 2 isoforms. (PMID:16504037)
• Our results suggest that protein sumoylation could play a pivotal role in controlling MEF2 transcriptional activity. (PMID:16563226)
• Mutations in exon 11 of MEF2A gene exist in the patients with coronary artery disease, and the mutations may be pathological. (PMID:16767660)
• Delta7aa mutation was not detected in any individual within the study population and is unlikely to play a significant role in the development of IHD in Ireland (PMID:16872533)
• The role of ACTN4 in MEF2A transcription via HDAC7 antagonism is reported. (PMID:16980305)
• The MEF2A gene could be involved in the risk of developing late-onset Alzheimer’s disease. (PMID:17112666)
• the CAG repeat polymorphism is associated with coronary heart disease in the Chinese population and the (CAG)9 allele may be an independent predictive factor for CAD (PMID:17579569)
• Overexpression of MEF2A is associated with hepatocellular carcinoma (PMID:17611778)
• Myocyte enhancer factor 2A is transcriptionally autoregulated in human and amphioxus (PMID:18073218)
• Studying independent samples of >1700 MI patients, 2 large control populations, and multiple families with apparently mendelian inheritance of the disease, no evidence was found for any linkage or association signal in the MEF2A gene. (PMID:18086930)
• no association between MEF2A gene and premature myocardial infarction. (PMID:18160598)
• These findings support a role for MEF2A as an intermediary in coordinating respiratory chain subunit expression in heart and muscle through a NRF1 –> MEF2A –> COX(H) transcriptional cascade. (PMID:18222924)
• These results suggest that the inhibitory effect of cAMP on IL-10 production by normal peripheral T lymphocytes is cell type and stimulus specific, exerted on multiple levels and involves MEF2 transcription factor. (PMID:19058854)
• MEF2 proteins are an important component in Galpha13-mediated angiogenesis. (PMID:19093215)
• No Chinese Taiwanese coronary patients had Pro279Leu & 21-bp deletion mutations in exons 7 & 11 respectively. The distribution of the allele frequencies of MEF2A exon 11 CAG repeat (CAG)n polymorphism was similar in both patients and controls. (PMID:19153100)
• rare MEF2A mutations did not contribute to the risk for LVH/HCM. However, the 11 repeats poly-Q allele could be a risk factor for LVH secondary to hypertension (PMID:19161138)
• novel interaction between the catalytic subunit of protein phosphatase 1alpha and MEF2A. Interaction occurs within the nucleus, and binding of PP1alpha to MEF2 potently represses MEF2-dependent transcription (PMID:19364819)
• These results identify MEF2A gene as a susceptibility gene for coronary artery disease. (PMID:19782985)
• TGF-beta transcriptionally upregulated MMP-10 through activation of MEF2A, concomitant with acetylation of core histones increasing around the promoter, as a consequence of degradation of the class IIa HDACs. (PMID:19935709)
• MEF2A is not a susceptibility gene for coronary artery disease and premature myocardial infarction in the Italian population. (PMID:20031581)
• The current structure suggests that the ligand-binding pocket is not induced by cofactor binding but rather preformed by intrinsic folding. (PMID:20132824)
• ZAC1 is a novel and previously unknown regulator of cardiomyocyte Glut4 expression and glucose uptake; MEF2 is a regulator of ZAC1 expression in response to induction of hypertrophy (PMID:20363751)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mef2aa	ENSDARG00000031756
mus_musculus	Mef2a	ENSMUSG00000030557
rattus_norvegicus	Mef2a	ENSRNOG00000047756

Paralogs (4): MEF2C (ENSG00000081189), SRF (ENSG00000112658), MEF2D (ENSG00000116604), MEF2B (ENSG00000213999)

Protein

Protein identifiers

Myocyte-specific enhancer factor 2A — Q02078 (reviewed: Q02078)

Alternative names: Serum response factor-like protein 1

All UniProt accessions (11): Q02078, A0A0S2Z417, A0A0S2Z453, A0A0S2Z454, A0A0S2Z4C8, A0A0S2Z4N0, A0A8I5KPE6, A0A8I5KVQ4, H0YKY6, H0YM62, H0YNI2

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which binds specifically to the MEF2 element, 5’-YTAATTAR-3’, found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation. Associates with chromatin to the ZNF16 promoter.

Subunit / interactions. Binds DNA as a homo- or heterodimer. Dimerizes with MEF2D. Interacts with HDAC7. Interacts with PIAS1; the interaction enhances sumoylation. Interacts with HDAC4, HDAC9 and SLC2A4RG. Interacts (via the N-terminal) with MAPK7; the interaction results in the phosphorylation and transcriptional activity of MEF2A.

Subcellular location. Nucleus.

Tissue specificity. Isoform MEF2 and isoform MEFA are expressed only in skeletal and cardiac muscle and in the brain. Isoform RSRFC4 and isoform RSRFC9 are expressed in all tissues examined.

Post-translational modifications. Constitutive phosphorylation on Ser-408 promotes Lys-403 sumoylation thus preventing acetylation at this site. Dephosphorylation on Ser-408 by PPP3CA upon neuron depolarization promotes a switch from sumoylation to acetylation on residue Lys-403 leading to inhibition of dendrite claw differentiation. Phosphorylation on Thr-312 and Thr-319 are the main sites involved in p38 MAPK signaling and activate transcription. Phosphorylated on these sites by MAPK14/p38alpha and MAPK11/p38beta, but not by MAPK13/p38delta nor by MAPK12/p38gamma. Phosphorylation on Ser-408 by CDK5 induced by neurotoxicity inhibits MEF2A transcriptional activation leading to apoptosis of cortical neurons. Phosphorylation on Thr-312, Thr-319 and Ser-355 can be induced by EGF. Sumoylation on Lys-403 is enhanced by PIAS1 and represses transcriptional activity. Phosphorylation on Ser-408 is required for sumoylation. Has no effect on nuclear location nor on DNA binding. Sumoylated with SUMO1 and, to a lesser extent with SUMO2 and SUMO3. PIASx facilitates sumoylation in postsynaptic dendrites in the cerebellar cortex and promotes their morphogenesis. Acetylation on Lys-403 activates transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation. Hyperacetylation by p300 leads to enhanced cardiac myocyte growth and heart failure. Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 3 and caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.

Disease relevance. Coronary artery disease, autosomal dominant, 1 (ADCAD1) [MIM:608320] A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the MEF2 family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q02078-1	MEF2	yes
Q02078-2	MEFA
Q02078-3	RSRFC4
Q02078-4	RSRFC9
Q02078-5	5
Q02078-6	6
Q02078-7	7
Q02078-8	8

RefSeq proteins (62): NP_001124398, NP_001124399, NP_001124400, NP_001165365, NP_001306135, NP_001339543, NP_001339544, NP_001339545, NP_001339546, NP_001339547, NP_001352130, NP_001352131, NP_001352132, NP_001352133, NP_001352134, NP_001352135, NP_001352136, NP_001352137, NP_001352138, NP_001352139, NP_001352140, NP_001380487, NP_001380488, NP_001380489, NP_001380490, NP_001386957, NP_001386958, NP_001386959, NP_001386960, NP_001386961, NP_001386962, NP_001386963, NP_001386964, NP_001386965, NP_001386966, NP_001386967, NP_001386968, NP_001386969, NP_001386978, NP_001386979, NP_001386980, NP_001386981, NP_001386982, NP_001386983, NP_001386984, NP_001386985, NP_001386986, NP_001386987, NP_001386988, NP_001386989, NP_001386990, NP_001386991, NP_001386992, NP_001386993, NP_001386994, NP_001386995, NP_001386996, NP_001386997, NP_001386998, NP_001386999, NP_001387000, NP_005578 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002100	TF_MADSbox	Domain
IPR022102	HJURP_C	Domain
IPR033896	MEF2-like_N	Domain
IPR036879	TF_MADSbox_sf	Homologous_superfamily

Pfam: PF00319, PF12347

UniProt features (74 total): mutagenesis site 19, modified residue 18, compositionally biased region 7, splice variant 6, region of interest 5, sequence variant 4, site 3, helix 3, strand 3, chain 1, domain 1, DNA-binding region 1, cross-link 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1EGW	X-RAY DIFFRACTION	1.5
6WC2	X-RAY DIFFRACTION	2.1
3P57	X-RAY DIFFRACTION	2.19
1LEW	X-RAY DIFFRACTION	2.3
6BYY	X-RAY DIFFRACTION	2.3
3MU6	X-RAY DIFFRACTION	2.43
3KOV	X-RAY DIFFRACTION	2.9
6BZ1	X-RAY DIFFRACTION	2.97
7XUZ	X-RAY DIFFRACTION	3.59
1C7U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02078-F1	55.90	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 176–177 (cleavage); 213–214 (cleavage); 466–467 (cleavage)

Post-translational modifications (19): 59, 98, 235, 249, 255, 312, 312, 319, 355, 403, 408, 415, 453, 403, 98, 98, 98, 30, 30

Mutagenesis-validated functional residues (19):

Position	Phenotype
176	abolishes cleavage at sites 1 and 2 by caspase 3. increased cleavage at site 3 by caspase 3.
213	abolishes cleavage at sites 2 and 3 by caspase 7.
255	slightly increased mef2a protein level.
255	decreased mef2a protein level.
269	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-270.
270	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-269.
273	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-275.
275	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-273.
277	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-278.
278	reduced p38 alpha- and beta2-mediated transcriptional activity; when associated with a-277.
312	greatly reduced p38-mediated phosphorylation. abolishes p38-mediated transcriptional activation; when associated with a-
319	greatly reduced p38-mediated phosphorylation. abolishes p38-mediated transcriptional activation; when associated with a-
355	no effect on p38-mediated transcriptional activity.
387	no effect on p38-mediated phosphorylation.
403	abolishes sumoylation. no change in subcellular location nor in dna binding. loss of transcriptional repression.
408	loss of sumoylation.
408	rescues sumoylation.
453	no effect on p38-mediated phosphorylation.
479	no effect on p38-mediated phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-198753	ERK/MAPK targets
R-HSA-525793	Myogenesis
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-448424	Interleukin-17 signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-450282	MAPK targets/ Nuclear events mediated by MAP kinases
R-HSA-450294	MAP kinase activation
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome

MSigDB gene sets: 429 (showing top): WENDT_COHESIN_TARGETS_UP, GOBP_DENDRITE_DEVELOPMENT, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_CARBOHYDRATE_TRANSPORT, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, TURJANSKI_MAPK7_TARGETS, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, EVI1_05, MARTINEZ_RB1_TARGETS_UP, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA-templated transcription (GO:0006351), apoptotic process (GO:0006915), heart development (GO:0007507), muscle organ development (GO:0007517), positive regulation of cardiac muscle hypertrophy (GO:0010613), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of D-glucose import across plasma membrane (GO:0046326), mitochondrion distribution (GO:0048311), dendrite morphogenesis (GO:0048813), muscle cell development (GO:0055001), ventricular cardiac myofibril assembly (GO:0055005), cardiac conduction (GO:0061337), cellular response to calcium ion (GO:0071277), obsolete mitochondrial genome maintenance (GO:0000002), MAPK cascade (GO:0000165), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), positive regulation of DNA-templated transcription (GO:0045893), animal organ development (GO:0048513), ERK5 cascade (GO:0070375)

GO Molecular Function (17): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), protein kinase binding (GO:0019901), histone acetyltransferase binding (GO:0035035), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), SMAD binding (GO:0046332), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Toll-like Receptor Cascades	7
Immune System	2
Toll Like Receptor 4 (TLR4) Cascade	2
Toll Like Receptor 2 (TLR2) Cascade	2
Nuclear Events (kinase and transcription factor activation)	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
Developmental Biology	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Signaling by Receptor Tyrosine Kinases	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
gene expression	2
animal organ development	2
regulation of gene expression	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
binding	2
enzyme binding	2
protein binding	2
negative regulation of DNA-templated transcription	1
RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
circulatory system development	1
muscle structure development	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
mitochondrion localization	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
muscle cell differentiation	1
cell development	1
cardiac myofibril assembly	1
ventricular cardiac muscle cell development	1
regulation of heart contraction	1
response to calcium ion	1
cellular response to metal ion	1
intracellular signaling cassette	1

Protein interactions and networks

STRING

2750 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEF2A	MYOD1	P15172	937
MEF2A	HDAC9	Q9UKV0	874
MEF2A	HDAC4	P56524	863
MEF2A	HDAC7	Q8WUI4	847
MEF2A	MYOG	P15173	846
MEF2A	HDAC1	Q13547	803
MEF2A	EP300	Q09472	793
MEF2A	MYF5	P13349	772
MEF2A	MAPK7	Q13164	755
MEF2A	XIRP2	A4UGR9	753
MEF2A	HDAC5	Q9UQL6	743
MEF2A	SLC2A4RG	Q9NR83	740
MEF2A	KLF15	Q9UIH9	738
MEF2A	HAND2	P61296	732
MEF2A	CABIN1	Q9Y6J0	732

IntAct

41 interactions, top by confidence:

A	B	Type	Score
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
Prkcq	Nfix	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
PITX2	MEF2A	psi-mi:“MI:0915”(physical association)	0.530
MEF2A	PITX2	psi-mi:“MI:0407”(direct interaction)	0.530
Nfix	MEF2A	psi-mi:“MI:0915”(physical association)	0.510
MEF2A	Nfix	psi-mi:“MI:0915”(physical association)	0.510
MEF2A	Hdac5	psi-mi:“MI:0915”(physical association)	0.490
MEF2A	HDAC4	psi-mi:“MI:0403”(colocalization)	0.490
MEF2A	HDAC4	psi-mi:“MI:0407”(direct interaction)	0.490
Dlg4	MEF2A	psi-mi:“MI:0407”(direct interaction)	0.440
MEF2A	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MEF2A	Myod1	psi-mi:“MI:0915”(physical association)	0.400
MEF2A	SUMO1	psi-mi:“MI:0915”(physical association)	0.400
MEF2A	Smarca4	psi-mi:“MI:0915”(physical association)	0.400
DDB1	MEF2A	psi-mi:“MI:0915”(physical association)	0.370
NDUFB9	MEF2A	psi-mi:“MI:0915”(physical association)	0.370
MEF2A	REV3L	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
KLC3	DCTN6	psi-mi:“MI:0914”(association)	0.350
MEF2A	PTPN5	psi-mi:“MI:0914”(association)	0.350
MEF2B	MEF2A	psi-mi:“MI:0914”(association)	0.350
AR	MED6	psi-mi:“MI:2364”(proximity)	0.270
MEF2A	PTMA	psi-mi:“MI:2364”(proximity)	0.270
SOX2	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SP7	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (112): HDAC3 (Affinity Capture-Western), HDAC5 (Affinity Capture-Western), HDAC7 (Affinity Capture-Western), HAND1 (Affinity Capture-Western), MEF2A (Reconstituted Complex), MEF2A (Affinity Capture-MS), MEF2A (Affinity Capture-MS), MEF2A (Affinity Capture-MS), MEF2A (Affinity Capture-MS), JUN (Affinity Capture-MS), ATF3 (Affinity Capture-MS), ATF7 (Affinity Capture-MS), CABIN1 (Affinity Capture-MS), HIST1H2BA (Affinity Capture-MS), MEF2C (Affinity Capture-MS)

ESM2 similar proteins: A0A096MJY4, A0A486WWJ9, A2ICN5, A2VDZ3, A4UTP7, A8WL06, B7ZR65, H2LBU8, O89038, P10071, P40791, P55197, P55879, Q02078, Q03413, Q03414, Q06413, Q0VGT2, Q14814, Q2KIA0, Q2MJT0, Q32NP8, Q4VYR7, Q5IS56, Q5R444, Q5REW7, Q5U4X3, Q60929, Q61602, Q63943, Q6DFF5, Q6DIF3, Q6F2E7, Q7ZY13, Q8BUR3, Q8CFN5, Q91660, Q91661, Q9DE25, Q9EPK5

Diamond homologs: A0A096MJY4, A0A217EJJ0, A0A3Q7EKL1, A2IB53, A2ICN5, A2VDZ3, A4UTP7, A9YDN6, B0XYE0, B4YPV4, B4YPW6, D7KQR8, D7KWY6, D7SMN6, F6I457, G4MWZ7, I1GN76, O22328, O55087, O65874, O89038, P0C5B0, P0C5B1, P0DI14, P29381, P29385, P29386, P35631, P38128, P40791, Q02078, Q02080, Q03413, Q03414, Q03489, Q06413, Q0J466, Q10CQ1, Q12224, Q14814

SIGNOR signaling

28 interactions.

A	Effect	B	Mechanism
CDK5	“down-regulates activity”	MEF2A	phosphorylation
NFATC2	up-regulates	MEF2A	binding
CABIN1	down-regulates	MEF2A
CDK4	down-regulates	MEF2A	binding
CyclinD/CDK4	down-regulates	MEF2A	binding
EP300	up-regulates	MEF2A	binding
MAPK7	up-regulates	MEF2A	phosphorylation
CAMK2D	up-regulates	MEF2A
MEF2A	up-regulates	Myoblast_fusion
MAPK11	“up-regulates activity”	MEF2A	phosphorylation
MEF2A	“up-regulates activity”	MYOD1	binding
MAPK14	“up-regulates activity”	MEF2A	phosphorylation
MAPK14	up-regulates	MEF2A	phosphorylation
HDAC4	down-regulates	MEF2A	binding
HDAC5	down-regulates	MEF2A	binding
MAPK14	unknown	MEF2A	phosphorylation
PHB2	down-regulates	MEF2A	binding
SMAD2	up-regulates	MEF2A	binding
PKCtheta/Nfix	“up-regulates activity”	MEF2A	phosphorylation
MEF2A	“up-regulates quantity by expression”	MYH2	“transcriptional regulation”
MEF2A	“up-regulates quantity by expression”	MYF6	“transcriptional regulation”
MEF2A	“up-regulates quantity by expression”	MYH1	“transcriptional regulation”
MEF2A	“up-regulates quantity by expression”	MYH10	“transcriptional regulation”
CARM1	up-regulates	MEF2A	methylation
MEF2A	“up-regulates quantity by expression”	SLC2A4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

78 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	37
Likely benign	9
Benign	14

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3242325	GRCh37/hg19 15q26.3(chr15:98615561-102400033)x1	Pathogenic
8948	NM_001319206.4(MEF2A):c.1313_1333del (p.Gln438_Pro444del)	Pathogenic
8949	NM_001319206.4(MEF2A):c.830C>T (p.Pro277Leu)	Pathogenic
8951	NM_001319206.4(MEF2A):c.842G>A (p.Gly281Asp)	Pathogenic

SpliceAI

3142 predictions. Top by Δscore:

Variant	Effect	Δscore
15:99598512:G:GG	donor_gain	1.0000
15:99632976:A:AG	acceptor_gain	1.0000
15:99632977:G:GG	acceptor_gain	1.0000
15:99632977:GA:G	acceptor_gain	1.0000
15:99632977:GAT:G	acceptor_gain	1.0000
15:99632977:GATC:G	acceptor_gain	1.0000
15:99633172:AGG:A	donor_loss	1.0000
15:99633174:GT:G	donor_loss	1.0000
15:99633175:T:A	donor_loss	1.0000
15:99671322:GA:G	acceptor_gain	1.0000
15:99671322:GACT:G	acceptor_gain	1.0000
15:99671450:GCCCT:G	donor_gain	1.0000
15:99671455:G:GG	donor_gain	1.0000
15:99671653:TCGCA:T	donor_gain	1.0000
15:99671654:CGCA:C	donor_gain	1.0000
15:99671655:GCA:G	donor_gain	1.0000
15:99671655:GCAG:G	donor_gain	1.0000
15:99671656:CA:C	donor_gain	1.0000
15:99671658:GTGA:G	donor_gain	1.0000
15:99671670:G:GG	donor_gain	1.0000
15:99674385:A:AG	acceptor_gain	1.0000
15:99674386:T:G	acceptor_gain	1.0000
15:99674389:A:AG	acceptor_gain	1.0000
15:99674390:C:G	acceptor_gain	1.0000
15:99674390:CAGCC:C	acceptor_loss	1.0000
15:99674391:A:AG	acceptor_gain	1.0000
15:99674391:AGCCT:A	acceptor_gain	1.0000
15:99674392:G:GC	acceptor_gain	1.0000
15:99674392:GC:G	acceptor_gain	1.0000
15:99674392:GCC:G	acceptor_gain	1.0000

AlphaMissense

3303 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000013641 (15:99660494 G>A), RS1000016963 (15:99691875 T>G), RS1000058580 (15:99596204 T>C), RS1000084674 (15:99641298 C>G), RS1000089563 (15:99644737 A>T), RS1000103431 (15:99579092 G>A,C), RS1000154453 (15:99578694 C>T), RS1000158481 (15:99691599 G>A), RS1000162964 (15:99619499 A>G), RS1000173159 (15:99686897 G>T), RS1000181963 (15:99566973 A>T), RS1000182249 (15:99580948 A>G), RS1000213910 (15:99565105 T>C), RS1000234605 (15:99613881 T>A,C), RS1000235538 (15:99658914 C>T)

Disease associations

OMIM: gene MIM:600660 | disease phenotypes: MIM:608320

GenCC curated gene-disease

Disease	Classification	Inheritance
coronary artery disease, autosomal dominant, 1	Limited	Autosomal dominant

Mondo (1): coronary artery disease, autosomal dominant, 1 (MONDO:0012011)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0001513	Obesity
HP:0001658	Myocardial infarction
HP:0003124	Hypercholesterolemia
HP:0003581	Adult onset
HP:0005181	Premature coronary artery atherosclerosis
HP:0100749	Chest pain

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004833_7	Cervical cancer	6.000000e-06
GCST004844_3	Gestational age at birth (maternal effect)	2.000000e-08
GCST006624_38	Systolic blood pressure	1.000000e-14
GCST007267_31	Systolic blood pressure	8.000000e-12
GCST009269_17	Dental caries (decayed and filled deciduous teeth)	2.000000e-06
GCST90002379_72	Basophil count	2.000000e-09
GCST90002380_35	Basophil percentage of white cells	3.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement
EFO:0006335	systolic blood pressure
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564258	Coronary Artery Disease, Autosomal Dominant, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases methylation, affects cotreatment	7
Tetrachlorodibenzodioxin	increases expression	3
Particulate Matter	increases abundance, increases expression, affects expression	3
bisphenol A	increases expression, increases methylation	2
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	2
Acetaminophen	increases expression	2
Acrolein	affects cotreatment, decreases expression, increases abundance	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases methylation, increases expression	2
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
geraniol	increases expression	1
trichostatin A	affects expression, decreases reaction	1
dimethylselenide	increases expression, increases oxidation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
ursodoxicoltaurine	decreases expression, decreases reaction	1
4-phenylbutyric acid	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
pinostrobin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4B9	SEES3-1V human MEF2A, clone1	Embryonic stem cell	Male
CVCL_A4C0	SEES3-1V human MEF2A, clone2	Embryonic stem cell	Male
CVCL_A4C1	SEES3-1V human MEF2A, clone3	Embryonic stem cell	Male
CVCL_B8KB	Abcam HCT 116 MEF2A KO	Cancer cell line	Male
CVCL_B9MK	Abcam A-549 MEF2A KO	Cancer cell line	Male
CVCL_D2GB	Abcam MCF-7 MEF2A KO	Cancer cell line	Female

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00846846	PHASE4	COMPLETED	PROTECT Continued Access Post Marketing Surveillance Trial