MRTFA

Summary

MRTFA (myocardin related transcription factor A, HGNC:14334) is a protein-coding gene on chromosome 22q13.1-q13.2, encoding Myocardin-related transcription factor A (Q969V6). Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration.

The protein encoded by this gene interacts with the transcription factor myocardin, a key regulator of smooth muscle cell differentiation. The encoded protein is predominantly nuclear and may help transduce signals from the cytoskeleton to the nucleus. This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57591 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 66 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 38
• Clinical variants (ClinVar): 958 total — 2 pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_020831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14334
Approved symbol	MRTFA
Name	myocardin related transcription factor A
Location	22q13.1-q13.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1438, MAL, MRTF-A, BSAC, MKL
Ensembl gene	ENSG00000196588
Ensembl biotype	protein_coding
OMIM	606078
Entrez	57591

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000355630, ENST00000402042, ENST00000402630, ENST00000407029, ENST00000422851, ENST00000463769, ENST00000466278, ENST00000477468, ENST00000614754, ENST00000620651, ENST00000650658, ENST00000651158, ENST00000651595, ENST00000651694, ENST00000652095, ENST00000673719, ENST00000699988

RefSeq mRNA: 5 — MANE Select: NM_020831 NM_001282660, NM_001282661, NM_001282662, NM_001318139, NM_020831

CCDS: CCDS14003, CCDS74865, CCDS74866, CCDS82720, CCDS93172

Canonical transcript exons

ENST00000355630 — 15 exons

Exon	Start	End
ENSE00000654903	40417341	40417493
ENSE00000654904	40418374	40419384
ENSE00000654905	40420405	40420576
ENSE00000654907	40420847	40421100
ENSE00000654908	40423536	40423685
ENSE00000654909	40424206	40424381
ENSE00000880410	40435499	40435554
ENSE00001177542	40594674	40594735
ENSE00001796368	40429606	40429767
ENSE00003607060	40463221	40463286
ENSE00003672504	40416986	40417046
ENSE00003786964	40431405	40431480
ENSE00003850803	40636478	40636719
ENSE00003850957	40552106	40552367
ENSE00003888727	40410289	40411907

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 93.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.4060 / max 937.1130, expressed in 1818 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194321	20.6724	1813
194311	6.4047	485
194318	1.4773	644
194317	0.4718	250
194319	0.2689	110
194316	0.1110	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	93.45	gold quality
leukocyte	CL:0000738	93.34	gold quality
mononuclear cell	CL:0000842	93.33	gold quality
granulocyte	CL:0000094	92.66	gold quality
popliteal artery	UBERON:0002250	91.83	gold quality
tibial artery	UBERON:0007610	91.82	gold quality
right testis	UBERON:0004534	91.00	gold quality
bone marrow cell	CL:0002092	90.94	gold quality
left testis	UBERON:0004533	90.83	gold quality
body of uterus	UBERON:0009853	90.82	gold quality
blood	UBERON:0000178	90.56	gold quality
aorta	UBERON:0000947	90.51	gold quality
stromal cell of endometrium	CL:0002255	90.39	gold quality
left uterine tube	UBERON:0001303	90.23	gold quality
sural nerve	UBERON:0015488	90.06	gold quality
endocervix	UBERON:0000458	89.54	gold quality
apex of heart	UBERON:0002098	89.41	gold quality
right frontal lobe	UBERON:0002810	89.27	gold quality
left coronary artery	UBERON:0001626	89.19	gold quality
tonsil	UBERON:0002372	89.16	gold quality
colonic epithelium	UBERON:0000397	89.03	gold quality
descending thoracic aorta	UBERON:0002345	89.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.99	gold quality
right coronary artery	UBERON:0001625	88.94	gold quality
coronary artery	UBERON:0001621	88.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.90	gold quality
thoracic aorta	UBERON:0001515	88.86	gold quality
lower esophagus	UBERON:0013473	88.86	gold quality
ascending aorta	UBERON:0001496	88.80	gold quality
spleen	UBERON:0002106	88.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.93

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
COL1A1	Activation
SCAI	Unknown
SRF	Unknown
TAGLN	Activation

Upstream regulators (CollecTRI, top): ELK1, FOS, FOXO1, SRF

miRNA regulators (miRDB)

71 targeting MRTFA, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4677-3P	99.49	67.91	1246

Literature-anchored findings (GeneRIF, showing 40)

• BSAC is a novel transcriptional activator with antiapoptotic function (PMID:12019265)
• Role of MKL1 in serum induction of c-fos and other SRE-regulated genes with a dominant negative MKL1 mutant (DN-MKL1) and RNA interference (RNAi) was assessed. DN-MKL1 and RNAi specifically blocked SRE-dependent reporter gene activation by serum and RhoA (PMID:12944485)
• MKL1 was predominantly cytoplasmic in C2C12 cells, with a small amount in the nucleus, however, no movement of MKL1 to the nucleus was observed upon differentiation. (PMID:14565952)
• MKL1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells (PMID:14970199)
• Microarray experiments using NIH3T3 cells expressing dominant negative human MKL1 identified SRF target genes whose activation is MKL-dependent. A subset of immediate early and SRF target genes are activated by the Rho-MKL pathway. (PMID:15329155)
• Fusion with RBM15 protein in acute myeloid leukemi. (PMID:15849773)
• results demonstrated that MKL1 is sumoylated and this modification represses transcriptional activity of MKL1. (PMID:16098147)
• Brg1/Brm containing SWI/SNF complexes play a critical role in regulating expression of SRF/MRTFA-dependent smooth muscle-specific genes but not SRF/MRTFA-dependent early response genes. (PMID:17599918)
• BMP signaling modulates VSMC phenotype via cross-talk with the RhoA/MRTFs pathway, and may contribute to the development of the pathological characteristics observed in patients with PAH and other obliterative vascular diseases. (PMID:17947237)
• Myocardin-related transcription factors are critical mediators of transforming growth factor beta (TGF-beta) 1-induced epithelial-mesenchymal transition.[ (PMID:18056415)
• MKL1 expression or activity may have a profound effect on myofibroblast formation and function in the kidney (PMID:18337547)
• RhoA/Rho-associated kinase signaling plays positive and negative roles in myogenic differentiation, mediated by MRTF-A/Smad-dependent transcription of the Id3 gene in a differentiation stage-specific manner (PMID:18477564)
• functional and spatial changes of OTT and BSAC caused by the fusion might perturb their functions, culminating in the development of acute megakaryoblastic leukemia. (PMID:18667423)
• Rho kinase-dependent activation of MRTF-A appears to act upstream of the myocardin pathway during smooth muscle cell differentiation of human adipose tissue-derived mesenchymal stem cells. (PMID:18688043)
• Serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation. (PMID:18694962)
• The deregulated activation of MAL-dependent and -independent promoters results in tissue-specific functions of OTT-MAL.[OTT-MAL] (PMID:18710951)
• Both RPEL peptides of the MAL protein bind to the G-actin hydrophobic cleft and to subdomain 3. (PMID:19008859)
• MKL1 oOverexpression in erythroleukemia cells increases the number of megakaryocytes with an increase in ploidy. Overexpression promotes megakaryocytic differentiation of primary CD34(+) cells cultured with thrombopoietin. MKL1 acts through SRF. (PMID:19136660)
• RNA interference was used to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, in which basal MRTF-SRF activity is Rho-dependent. (PMID:19198601)
• single nucleotide polymorphism in the megakaryoblastic leukemia factor-1 gene is associated with coronary artery disease. (PMID:19513752)
• MAL expression increases during the late differentiation steps of neonate and adult megakaryopoiesis and localized into the nucleus after Rho GTPase activation (PMID:19724058)
• Presents evidence that strongly suggests a dual role for MKL1 in oncogenic mechanisms, as a tumor-promoting or tumor-suppressing molecule. (PMID:20816842)
• Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury. (PMID:21330600)
• MRTF-A is an important regulator of collagen synthesis in lung fibroblasts and exhibits a dependence on both SRF and Sp1 function to enhance collagen expression (PMID:22049076)
• study provides evidence that MKL1/2 mediates cancerous transformation in DLC1-deficient hepatocellular and mammary carcinoma cells (PMID:22139079)
• molecular inhibitory pathway linking BMP4 signaling, activation of MRTF-A, and inhibition of NF-kappaB provides insights into the etiology of PAH and a potential focus of therapeutic intervention. (PMID:22718766)
• both Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein interact with the Setd1b histone H3-Lys4 methyltransferase (PMID:22927943)
• force-induced polymerization of actin and changes in the F/G actin ratio resulting in nuclear translocation of the G-actin-associated transcriptional cofactor, megakaryoblastic acute leukemia factor-1 (PMID:23062334)
• in megakaryocytes, subcellular localization and regulation of MKL1 is dependent on RhoA activity and actin organization (PMID:23243284)
• Constitutional deletion in MKL1 gene is associated with Hodgkin lymphoma. (PMID:23744493)
• Tbeta4 competes with myocardin-related transcription factor (MRTF)-A for G-actin binding, thus interfering with G-actin-MRTF-A complex formation. (PMID:23811404)
• MKL1/2 depletion resulted in Ras activation, elevated p16 expression and hypophosphorylation of the retinoblastoma (Rb) protein in DLC1-deficient hepatocellular carcinoma cells. (PMID:23853104)
• The data identify the GEF Bcr as a regulator of RhoA/MAL signaling in keratinocytes, which in turn promotes differentiation through the desmosomal cadherin Dsg1. (PMID:23940119)
• results provided novel evidence supporting the metastasis-promoting functions of MRTF-A, and implied that MRTF-A might be a switch for the estrogen pathway to change its proliferation-promoting roles into migration-stimulating roles in breast cancer (PMID:24084383)
• Data suggest that megakaryoblastic leukemia 1 (MKL1) and histone acetyltransferase p300 could augment the expression of catechol-O-methyltransferase (COMT), increase estrogen metabolism, and thus reduce MCF-7 cell proliferation stimulated by estrogen. (PMID:24096006)
• Overexpression of SMYD3 promotes MRTF-A-mediated upregulation of MYL9 and migration of MCF-7 breast cancer cells (PMID:24189459)
• TGFB1-mediated induction of the short MKL1 isoform initiates progression to later stages of differentiation towards a stationary myofibroblast. (PMID:24424023)
• This study highlights a crucial role for the transcriptional regulator Mkl1 and its SAP domain during breast cancer progression (PMID:24495796)
• We conclude that the -184C>T of MKL1 is an important susceptibility factor for CAD in the Han Chinese in Henan Province (PMID:24615024)
• Activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. (PMID:24721635)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mrtfaa	ENSDARG00000075867
danio_rerio	mrtfab	ENSDARG00000076229
mus_musculus	Mrtfa	ENSMUSG00000042292
rattus_norvegicus	Mrtfa	ENSRNOG00000018803
drosophila_melanogaster	Mrtf	FBGN0052296
caenorhabditis_elegans		WBGENE00004145

Paralogs (2): MYOCD (ENSG00000141052), MRTFB (ENSG00000186260)

Protein

Protein identifiers

Myocardin-related transcription factor A — Q969V6 (reviewed: Q969V6)

Alternative names: MKL/myocardin-like protein 1, Megakaryoblastic leukemia 1 protein, Megakaryocytic acute leukemia protein

All UniProt accessions (13): Q969V6, A0A087WU73, A0A087X287, A0A494BZX7, A0A494C0Z8, A0A494C1G6, A0A499FIJ6, A0A669KBG1, A0A8V8TPQ1, B0QY74, B0QY83, B0QY84, W0Z7M9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration. The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. MRTFA binds G-actin via its RPEL repeats, regulating activity of the MRTFA-SRF complex. Activity is also regulated by filamentous actin (F-actin) in the nucleus.

Subunit / interactions. Interacts with SRF, forming the SRF-MRTFA nuclear complex which binds the 5’-CArG-3’ consensus motif (CArG box) on DNA via SRF. Interacts (via RPEL repeats) with globular actin (G-actin), thereby regulating its subcellular location and activity of the complex formed with SRF. Either forms a trivalent (by binding three G-actin monomers) or pentavalent (by binding five G-actin monomers) complex with G-actin. Forms a nuclear ternary complex with SCAI and SRF, leading to suppress MRTFA-induced SRF transcriptional activity. Interacts with beta-actin (ACTB); interaction with ACTB prevents interaction with SCAI. Interacts with MRTFB.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitously expressed, has been detected in lung, placenta, small intestine, liver, kidney, spleen, thymus, colon, muscle, heart and brain. Expressed in peripheral blood mononuclear cells (at protein level).

Post-translational modifications. Phosphorylation at Ser-6 by Erk inhibits binding of globular actin (G-actin), unmasking the nuclear localization signal (NLS) and promoting nuclear import.

Disease relevance. A chromosomal aberration involving MRTFA may be a cause of acute megakaryoblastic leukemia. Translocation t(1;22)(p13;q13) with RBM15. Although both reciprocal fusion transcripts are detected in acute megakaryoblastic leukemia (AMKL, FAB-M7), the RBM15-MRTFA chimeric protein has all the putative functional domains encoded by each gene and is the candidate oncogene. Immunodeficiency 66 (IMD66) [MIM:618847] An autosomal recessive primary immunologic disorder characterized by recurrent viral infections from infancy, associated with impaired neutrophil migration due to defects in cytoskeletal actin dynamics. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal region is required for nuclear localization and the C-terminal region mediates transcriptional activity. The RPEL repeats mediate binding to globular actin (G-actin); each RPEL repeat-binding to one G-actin monomer. In addition, each intervening spacer sequence region can bind one G-actin monomer, to reach a pentavalent complex.

RefSeq proteins (5): NP_001269589, NP_001269590, NP_001269591, NP_001305068, NP_065882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003034	SAP_dom	Domain
IPR004018	RPEL_repeat	Repeat
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR043451	Myocardin-like	Family

Pfam: PF02037, PF02755

UniProt features (62 total): modified residue 29, compositionally biased region 10, region of interest 9, repeat 2, sequence variant 2, helix 2, strand 2, chain 1, coiled-coil region 1, short sequence motif 1, site 1, domain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2KVU	SOLUTION NMR
2KW9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969V6-F1	56.59	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 (1): 3–4 (breakpoint for translocation to form rbm15-mrtfa)

Post-translational modifications (29): 6, 124, 139, 156, 305, 310, 312, 313, 317, 320, 333, 385, 446, 447, 449, 450, 454, 456, 458, 482 …

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 507 (showing top): GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MODULE_169, BIOCARTA_MAL_PATHWAY, LU_IL4_SIGNALING, GGGNRMNNYCAT_UNKNOWN, JAEGER_METASTASIS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, MODULE_45, MODULE_64, AREB6_03, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP

GO Biological Process (27): actin cytoskeleton organization (GO:0030036), wound healing, spreading of cells (GO:0044319), positive regulation of transcription by RNA polymerase II (GO:0045944), smooth muscle cell differentiation (GO:0051145), positive regulation of miRNA transcription (GO:1902895), neuron migration (GO:0001764), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cardiac muscle hypertrophy (GO:0010613), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), positive regulation of actin filament polymerization (GO:0030838), forebrain development (GO:0030900), neuron projection development (GO:0031175), positive regulation of collagen biosynthetic process (GO:0032967), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of endothelial cell differentiation (GO:0045603), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of hepatic stellate cell migration (GO:0061870), positive regulation of hepatic stellate cell contraction (GO:0061874), cellular response to retinoic acid (GO:0071300), cellular response to transforming growth factor beta stimulus (GO:0071560), regulation of modification of postsynaptic structure (GO:0099159), cellular response to angiotensin (GO:1904385), response to amyloid-beta (GO:1904645), positive regulation of hepatic stellate cell proliferation (GO:1904899), positive regulation of hepatic stellate cell activation (GO:2000491), negative regulation of apoptotic signaling pathway (GO:2001234)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), actin binding (GO:0003779), actin monomer binding (GO:0003785), leucine zipper domain binding (GO:0043522), transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity (GO:0003700), protein phosphatase inhibitor activity (GO:0004864), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1
RHO GTPase Effectors	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
positive regulation of DNA-templated transcription	3
regulation of DNA-templated transcription	3
synapse	3
cell migration	2
transcription by RNA polymerase II	2
cytoskeleton organization	1
actin filament-based process	1
epiboly involved in wound healing	1
regulation of transcription by RNA polymerase II	1
muscle cell differentiation	1
miRNA transcription	1
regulation of miRNA transcription	1
positive regulation of miRNA metabolic process	1
generation of neurons	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
brain development	1
anatomical structure development	1
neuron development	1
plasma membrane bounded cell projection organization	1
positive regulation of biosynthetic process	1
positive regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
positive regulation of epithelial cell differentiation	1
endothelial cell differentiation	1
regulation of endothelial cell differentiation	1

Protein interactions and networks

STRING

2805 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRTFA	SRF	P11831	992
MRTFA	RBM15	Q96T37	953
MRTFA	PHACTR1	Q9C0D0	898
MRTFA	RHOA	P06749	777
MRTFA	MYOCD	Q8IZQ8	766
MRTFA	WDR5	P61964	733
MRTFA	TAGLN	Q01995	677
MRTFA	TRIM8	Q9BZR9	660
MRTFA	SMARCA4	P51532	648
MRTFA	EMD	P50402	627
MRTFA	EP300	Q09472	557
MRTFA	KMT2A	Q03164	554
MRTFA	ZFPM1	Q8IX07	548
MRTFA	HERC5	Q9UII4	544
MRTFA	KDM3A	Q9Y4C1	521

IntAct

46 interactions, top by confidence:

A	B	Type	Score
BCL7A	ARID1A	psi-mi:“MI:0914”(association)	0.640
MRTFA	SRF	psi-mi:“MI:0915”(physical association)	0.590
SRF	MRTFA	psi-mi:“MI:0915”(physical association)	0.590
FLNA	LPAR1	psi-mi:“MI:0914”(association)	0.580
LPAR1	FLNA	psi-mi:“MI:0914”(association)	0.580
MRTFA	FLNA	psi-mi:“MI:2364”(proximity)	0.570
MRTFA	FLNA	psi-mi:“MI:0914”(association)	0.570
FLNA	MRTFA	psi-mi:“MI:0915”(physical association)	0.570
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
MRTFA	LPAR1	psi-mi:“MI:2364”(proximity)	0.500
LPAR1	MRTFA	psi-mi:“MI:2364”(proximity)	0.500
MAP1LC3B	MRTFA	psi-mi:“MI:0407”(direct interaction)	0.440
MAP1LC3A	MRTFA	psi-mi:“MI:0407”(direct interaction)	0.440
MRTFA	FUNDC2	psi-mi:“MI:0915”(physical association)	0.400
MRTFA	MRTFB	psi-mi:“MI:0915”(physical association)	0.400
KPNA3	MRTFA	psi-mi:“MI:0915”(physical association)	0.400
CXCL9	MRTFA	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BCL7A	DPF1	psi-mi:“MI:0914”(association)	0.350
MAPK1	SEC16A	psi-mi:“MI:0914”(association)	0.350
CUL4B	GGTLC3	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350

BioGRID (72): MKL1 (Reconstituted Complex), MKL1 (Affinity Capture-RNA), MKL1 (Reconstituted Complex), MKL1 (Proximity Label-MS), MKL1 (Proximity Label-MS), MKL1 (Proximity Label-MS), MKL1 (Proximity Label-MS), MKL1 (Proximity Label-MS), MKL1 (Proximity Label-MS), MKL1 (Affinity Capture-MS), MKL1 (Affinity Capture-Western), EP300 (Affinity Capture-Western), MKL1 (Affinity Capture-Western), MKL1 (Affinity Capture-MS), MKL1 (Affinity Capture-RNA)

ESM2 similar proteins: A0JLT2, A4QNZ7, A5PK23, B1AZP2, F5HSE3, O60293, O75420, O95402, P61129, P78312, P97839, Q03111, Q07FY3, Q08C81, Q08DM1, Q174D3, Q1LVC2, Q32NP7, Q3T044, Q4G0F8, Q5EAY2, Q5F368, Q5R8Q8, Q5U2R6, Q6DD45, Q6DRL8, Q6PEI3, Q7TN02, Q80Z38, Q8C1B1, Q8C1S0, Q8CFT2, Q8CGI1, Q8IVL1, Q8K4J6, Q90YL3, Q90YY5, Q969V6, Q96A73, Q99MR1

Diamond homologs: P59759, Q8AYC1, Q8AYC2, Q8IZQ8, Q8K4J6, Q8R5I7, Q969V6, Q9ULH7, A7E346, Q0ZCJ7, Q6ZN01, Q7YR76, Q8VIM5

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
BMP4	up-regulates	MRTFA
MRTFA	down-regulates	KLF4
MRTFA	up-regulates	SRF	binding
MAPK1	down-regulates	MRTFA	phosphorylation
MAPK3	down-regulates	MRTFA	phosphorylation
Gbeta	down-regulates	MRTFA	phosphorylation
ERK1/2	down-regulates	MRTFA	phosphorylation
PKN1	“down-regulates activity”	MRTFA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Diseases of signal transduction by growth factor receptors and second messengers	5	8.4×	5e-03
Signaling by Receptor Tyrosine Kinases	5	7.6×	6e-03
Infectious disease	7	5.1×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	6	9.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	545
Likely benign	338
Benign	25

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3362871	A109D	Pathogenic
869135	NM_020831.6(MRTFA):c.2467A>T (p.Lys823Ter)	Pathogenic

SpliceAI

3734 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40416987:T:TA	donor_gain	1.0000
22:40417042:TTTTC:T	acceptor_gain	1.0000
22:40417044:TTCCT:T	acceptor_loss	1.0000
22:40417045:TC:T	acceptor_gain	1.0000
22:40417045:TCCTG:T	acceptor_loss	1.0000
22:40417046:CC:C	acceptor_gain	1.0000
22:40417047:C:CC	acceptor_gain	1.0000
22:40417336:CTCA:C	donor_loss	1.0000
22:40417337:TCAC:T	donor_loss	1.0000
22:40417338:CA:C	donor_loss	1.0000
22:40417339:A:C	donor_loss	1.0000
22:40417340:CCTG:C	donor_gain	1.0000
22:40419383:ACCT:A	acceptor_loss	1.0000
22:40419384:CCTGC:C	acceptor_loss	1.0000
22:40420400:TGTAC:T	donor_loss	1.0000
22:40420401:GTACC:G	donor_loss	1.0000
22:40420402:TA:T	donor_loss	1.0000
22:40420403:ACC:A	donor_loss	1.0000
22:40420404:C:CA	donor_loss	1.0000
22:40420572:CTGAC:C	acceptor_gain	1.0000
22:40420577:C:CC	acceptor_gain	1.0000
22:40420577:CTGGG:C	acceptor_loss	1.0000
22:40420842:CCTAC:C	donor_loss	1.0000
22:40420843:CTA:C	donor_loss	1.0000
22:40420844:TA:T	donor_loss	1.0000
22:40420845:A:AC	donor_gain	1.0000
22:40420845:A:C	donor_loss	1.0000
22:40420846:C:CG	donor_gain	1.0000
22:40420846:CT:C	donor_gain	1.0000
22:40421096:CTTTG:C	acceptor_gain	1.0000

AlphaMissense

6646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40419320:A:G	L373P	1.000
22:40419362:A:G	L359P	1.000
22:40419374:A:G	L355P	1.000
22:40420919:A:G	L270P	1.000
22:40429659:A:G	L83P	1.000
22:40429676:C:A	R77S	1.000
22:40429676:C:G	R77S	1.000
22:40429677:C:A	R77M	1.000
22:40429677:C:G	R77T	1.000
22:40429698:A:G	L70P	1.000
22:40429698:A:T	L70H	1.000
22:40429710:A:G	L66P	1.000
22:40429717:C:G	A64P	1.000
22:40429721:C:A	K62N	1.000
22:40429721:C:G	K62N	1.000
22:40429725:A:G	L61P	1.000
22:40431413:A:C	I44S	1.000
22:40431413:A:G	I44T	1.000
22:40431413:A:T	I44N	1.000
22:40431428:A:G	L39P	1.000
22:40431455:A:G	I30T	1.000
22:40431457:C:A	K29N	1.000
22:40431457:C:G	K29N	1.000
22:40431467:A:G	L26P	1.000
22:40431467:A:T	L26H	1.000
22:40435532:A:C	F10L	1.000
22:40435532:A:T	F10L	1.000
22:40435534:A:G	F10L	1.000
22:40417000:A:G	L755P	0.999
22:40417012:A:G	L751P	0.999

dbSNP variants (sampled 300 via entrez): RS1000019466 (22:40511260 A>T), RS1000033604 (22:40574823 G>T), RS1000036088 (22:40580785 GTGTT>G), RS1000037480 (22:40594622 A>C), RS1000040486 (22:40578718 T>A), RS1000080235 (22:40423337 A>T), RS1000080313 (22:40437137 G>A), RS1000090353 (22:40503804 C>A), RS1000095918 (22:40463589 T>C), RS1000103967 (22:40617890 A>G), RS1000146388 (22:40478407 C>T), RS1000170090 (22:40449799 A>G), RS1000170279 (22:40481655 A>C), RS1000179497 (22:40627587 A>G), RS1000185557 (22:40534749 T>A,C)

Disease associations

OMIM: gene MIM:606078 | disease phenotypes: MIM:618847, MIM:620978

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 66	Moderate	Autosomal recessive
leukodystrophy, hypomyelinating, 28	Moderate	Autosomal recessive

Mondo (2): immunodeficiency 66 (MONDO:0030013), leukodystrophy, hypomyelinating, 28 (MONDO:0975833)

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001287	Meningitis
HP:0001581	Recurrent skin infections
HP:0031379	Abnormal T cell proliferation
HP:0100806	Sepsis
HP:0200039	Pustule
HP:0410017	Otitis externa

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000431_3	Height	4.000000e-06
GCST001402_5	Treatment response for severe sepsis	6.000000e-07
GCST001585_27	Breast size	5.000000e-07
GCST001930_13	Breast cancer	2.000000e-06
GCST001937_22	Breast cancer	9.000000e-19
GCST002667_12	Mammographic density (dense area)	2.000000e-13
GCST003985_10	Breast size	3.000000e-12
GCST004521_42	Autism spectrum disorder or schizophrenia	1.000000e-08
GCST004988_19	Breast cancer	4.000000e-34
GCST005194_213	Coronary artery disease	3.000000e-08
GCST005951_24	Body mass index	2.000000e-08
GCST005984_20	Glomerular filtration rate	7.000000e-13
GCST005985_10	Creatinine levels	2.000000e-13
GCST006014_31	Creatine kinase levels	3.000000e-09
GCST006462_48	Uterine fibroids	5.000000e-09
GCST006655_11	Breast size	7.000000e-07
GCST006921_10	Regular attendance at a pub or social club	3.000000e-10
GCST007201_269	Schizophrenia	1.000000e-08
GCST007201_411	Schizophrenia	2.000000e-06
GCST007344_132	Estimated glomerular filtration rate	7.000000e-15
GCST007344_37	Estimated glomerular filtration rate	2.000000e-16
GCST007344_68	Estimated glomerular filtration rate	1.000000e-06
GCST008058_167	Estimated glomerular filtration rate	1.000000e-37
GCST008059_141	Estimated glomerular filtration rate	1.000000e-28
GCST008060_3	Estimated glomerular filtration rate	3.000000e-09
GCST008103_42	Bipolar disorder	2.000000e-07
GCST008115_35	Bipolar I disorder	3.000000e-07
GCST008595_230	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-08
GCST008745_32	Estimated glomerular filtration rate in non-diabetics	2.000000e-08
GCST008747_52	Estimated glomerular filtration rate	3.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0004340	body mass index
EFO:0004534	creatine kinase measurement
EFO:0009592	social interaction measurement
EFO:0009963	bipolar I disorder
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, decreases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
coumarin	affects phosphorylation	1
jasplakinolide	affects localization	1
exoenzyme C3, Clostridium botulinum	affects localization, decreases reaction	1
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	affects localization, decreases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
CCG 1423	affects localization, decreases reaction	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
MK-8776	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1

Cellosaurus cell lines

3 cell lines: 1 cancer cell line, 1 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C3IQ	1321N1 MRTFA KO	Cancer cell line	Male
CVCL_JL69	H9 RM	Embryonic stem cell	Female
CVCL_JL71	PBMC2-iPS4F8 RM	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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