DMRTA2

Summary

DMRTA2 (DMRT like family A2, HGNC:13908) is a protein-coding gene on chromosome 1p32.3, encoding Doublesex- and mab-3-related transcription factor A2 (Q96SC8). May be involved in sexual development.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II and sex differentiation. Predicted to act upstream of or within several processes, including nervous system development; positive regulation of neuroblast proliferation; and stem cell fate specification. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 63950 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Limited, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 92 total
• MANE Select transcript: NM_032110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13908
Approved symbol	DMRTA2
Name	DMRT like family A2
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	DMRT5
Ensembl gene	ENSG00000142700
Ensembl biotype	protein_coding
OMIM	614804
Entrez	63950

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000404795, ENST00000418121, ENST00000948348

RefSeq mRNA: 1 — MANE Select: NM_032110 NM_032110

CCDS: CCDS44141

Canonical transcript exons

ENST00000404795 — 3 exons

Exon	Start	End
ENSE00001456151	50417550	50419734
ENSE00001552910	50423116	50423443
ENSE00001557667	50420978	50421544

Expression profiles

Bgee: expression breadth broad, 54 present calls, max score 91.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7637 / max 57.2850, expressed in 169 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12271	0.6323	151
12272	0.1079	57
12270	0.0235	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	91.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.27	silver quality
buccal mucosa cell	CL:0002336	88.34	gold quality
ganglionic eminence	UBERON:0004023	86.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.04	gold quality
nasal cavity epithelium	UBERON:0005384	79.46	gold quality
palpebral conjunctiva	UBERON:0001812	79.07	gold quality
nasal cavity mucosa	UBERON:0001826	76.79	gold quality
lower esophagus mucosa	UBERON:0035834	63.07	gold quality
epithelium of nasopharynx	UBERON:0001951	63.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	63.00	silver quality
trachea	UBERON:0003126	61.47	silver quality
adenohypophysis	UBERON:0002196	61.00	gold quality
esophagus mucosa	UBERON:0002469	60.40	gold quality
pituitary gland	UBERON:0000007	60.38	gold quality
cortical plate	UBERON:0005343	57.68	gold quality
esophagus squamous epithelium	UBERON:0006920	55.41	gold quality
tendon of biceps brachii	UBERON:0008188	55.09	silver quality
medial globus pallidus	UBERON:0002477	52.60	gold quality
cartilage tissue	UBERON:0002418	52.57	gold quality
decidua	UBERON:0002450	52.33	gold quality
sperm	CL:0000019	51.95	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	51.91	gold quality
spinal cord	UBERON:0002240	50.82	gold quality
adult organism	UBERON:0007023	50.28	gold quality
globus pallidus	UBERON:0001875	49.87	gold quality
right testis	UBERON:0004534	49.87	gold quality
colonic epithelium	UBERON:0000397	49.64	gold quality
left testis	UBERON:0004533	49.29	gold quality
amniotic fluid	UBERON:0000173	49.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.59

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NEUROG1

JASPAR motifs

Motif	Name	Family
MA1478.1	DMRTA2	DMRT factors
MA1478.2	DMRTA2	DMRT factors

JASPAR matrix evidence (PMIDs): PMID:25215497

miRNA regulators (miRDB)

56 targeting DMRTA2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868

Literature-anchored findings (GeneRIF, showing 3)

• This study reveals, for the first time, the requirement of DMRTA2 for normal human female embryonic germ cell development. (PMID:25082981)
• Data suggest that loss of function of doublesex and mab-3-related transcription factor a2 (DMRTA2) leads to disorder of cortical development. (PMID:26757254)
• DMRTA2 supports glioma stem-cell mediated neovascularization in glioblastoma. (PMID:38509074)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dmrta2	ENSDARG00000039412
mus_musculus	Dmrta2	ENSMUSG00000047143
rattus_norvegicus	Dmrta2	ENSRNOG00000068045
caenorhabditis_elegans		WBGENE00019521
caenorhabditis_elegans		WBGENE00022060

Paralogs (8): DMRT3 (ENSG00000064218), DMRT1 (ENSG00000137090), DMRTC2 (ENSG00000142025), DMRTB1 (ENSG00000143006), DMRT2 (ENSG00000173253), DMRTA1 (ENSG00000176399), DMRTC1B (ENSG00000184911), DMRTC1 (ENSG00000269502)

Protein

Protein identifiers

Doublesex- and mab-3-related transcription factor A2 — Q96SC8 (reviewed: Q96SC8)

Alternative names: Doublesex- and mab-3-related transcription factor 5

All UniProt accessions (1): Q96SC8

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in sexual development.

Subcellular location. Nucleus.

Tissue specificity. Expressed in testis.

Similarity. Belongs to the DMRT family.

RefSeq proteins (1): NP_115486* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001275	DM_DNA-bd	Domain
IPR005173	DMA	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR026607	DMRT	Family
IPR036407	DM_DNA-bd_sf	Homologous_superfamily
IPR046472	DMRT5_1_DMB_dom	Domain

Pfam: PF00751, PF03474, PF20624

UniProt features (4 total): chain 1, domain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96SC8-F1	57.64	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 102 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NEUROBLAST_PROLIFERATION, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_REGIONALIZATION, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_NEURON_FATE_SPECIFICATION, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT

GO Biological Process (11): positive regulation of neuroblast proliferation (GO:0002052), regulation of transcription by RNA polymerase II (GO:0006357), neuroblast proliferation (GO:0007405), sex differentiation (GO:0007548), cerebral cortex regionalization (GO:0021796), skeletal muscle cell differentiation (GO:0035914), neuron fate specification (GO:0048665), stem cell fate specification (GO:0048866), dopaminergic neuron differentiation (GO:0071542), regulation of DNA-templated transcription (GO:0006355), stem cell differentiation (GO:0048863)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), identical protein binding (GO:0042802), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
cell fate specification	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
generation of neurons	1
neural precursor cell proliferation	1
developmental process involved in reproduction	1
regionalization	1
telencephalon regionalization	1
cerebral cortex development	1
skeletal muscle tissue development	1
neuron fate commitment	1
stem cell fate commitment	1
neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
protein binding	1
cation binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DMRTA2	EMX2	Q04743	523
DMRTA2	FOXL1	Q12952	507
DMRTA2	NFIA	Q12857	498
DMRTA2	HMBOX1	Q6NT76	453
DMRTA2	FAF1	Q9UNN5	445
DMRTA2	SLC18B1	Q6NT16	444
DMRTA2	FOXL3	A0A1W2PRP0	409
DMRTA2	EMX1	Q04741	399
DMRTA2	SPI1	P17947	390
DMRTA2	DMRT3	Q9NQL9	372
DMRTA2	LMX1A	Q8TE12	364
DMRTA2	NEUROG2	Q9H2A3	342
DMRTA2	GSX2	Q9BZM3	342
DMRTA2	PAX6	P26367	340
DMRTA2	AMH	P03971	337

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A2K3DDJ2, A2A9A2, A2VDX9, A2Y5N0, A4GRC6, A6QQ94, A8ICS9, A8ID95, A8INQ0, A8ITB0, A8ITV9, A8J666, A8JID5, F5A894, O83683, P09695, P09715, P14348, P17473, P24096, P28925, P30662, P54817, Q01JD1, Q08354, Q08355, Q08356, Q10MB4, Q2QPW2, Q49I55, Q49I57, Q4VKB4, Q5QD03, Q6AYU4, Q6F5E0, Q6L4N4, Q6S6U0, Q6SVX2, Q6SW04, Q7XT42

Diamond homologs: A2A9A2, A2A9I7, A4QNP7, A6QQ94, A8TSS9, B0I1G7, B7ZS42, C0LZJ1, D4A218, F6W2R2, G5EEJ1, J7FCF0, O18214, P23023, P57690, P83758, P85119, Q18248, Q19291, Q2I327, Q2MJB4, Q32LE6, Q3LH63, Q4AE28, Q5UU75, Q5VZB9, Q6YHU8, Q71MM5, Q76L87, Q801F8, Q80WT2, Q8BG36, Q8CFG4, Q8CGW9, Q8IXT2, Q8JIR6, Q90WM5, Q96MA1, Q96SC8, Q9DFI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

265 predictions. Top by Δscore:

Variant	Effect	Δscore
1:50419733:CT:C	acceptor_gain	1.0000
1:50419735:C:CC	acceptor_gain	1.0000
1:50419730:GGCCT:G	acceptor_gain	0.9900
1:50419731:GCCT:G	acceptor_gain	0.9900
1:50419732:CCTC:C	acceptor_gain	0.9900
1:50419735:C:CA	acceptor_loss	0.9900
1:50420975:CA:C	donor_loss	0.9900
1:50419731:GCCTC:G	acceptor_gain	0.9800
1:50419732:CCTCT:C	acceptor_gain	0.9600
1:50419733:CTCT:C	acceptor_gain	0.9100
1:50419735:C:G	acceptor_gain	0.9100
1:50420978:C:G	donor_loss	0.9100
1:50419732:CCT:C	acceptor_gain	0.9000
1:50419733:CTC:C	acceptor_gain	0.9000
1:50419734:TCT:T	acceptor_gain	0.9000
1:50420976:A:AC	donor_gain	0.8200
1:50420977:C:CC	donor_gain	0.8200
1:50420588:T:TA	donor_gain	0.7800
1:50420985:C:CA	donor_gain	0.7800
1:50419733:C:T	acceptor_gain	0.7600
1:50417776:C:CT	acceptor_gain	0.7400
1:50420981:AGCCC:A	donor_gain	0.7300
1:50419736:T:G	acceptor_gain	0.7100
1:50420098:A:C	donor_gain	0.7100
1:50419746:GAAAA:G	acceptor_gain	0.6900
1:50417773:A:T	acceptor_gain	0.6800
1:50419737:G:C	acceptor_gain	0.6700
1:50419744:GAGAA:G	acceptor_gain	0.6400
1:50419745:AGAAA:A	acceptor_gain	0.6400
1:50419701:T:TG	acceptor_gain	0.6200

AlphaMissense

3379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:50419254:A:T	I347N	1.000
1:50419258:C:G	A346P	1.000
1:50419299:A:G	L332P	1.000
1:50419322:G:C	F324L	1.000
1:50419322:G:T	F324L	1.000
1:50419323:A:C	F324C	1.000
1:50419323:A:G	F324S	1.000
1:50419324:A:G	F324L	1.000
1:50419335:A:C	L320W	1.000
1:50419335:A:G	L320S	1.000
1:50421173:C:T	E122K	1.000
1:50421179:C:G	A120P	1.000
1:50421181:T:G	Q119P	1.000
1:50421184:T:G	Q118P	1.000
1:50421186:C:A	R117S	1.000
1:50421186:C:G	R117S	1.000
1:50421187:C:A	R117M	1.000
1:50421187:C:G	R117T	1.000
1:50421188:T:A	R117W	1.000
1:50421188:T:C	R117G	1.000
1:50421190:C:G	R116P	1.000
1:50421191:G:T	R116S	1.000
1:50421193:A:C	L115R	1.000
1:50421193:A:G	L115P	1.000
1:50421193:A:T	L115Q	1.000
1:50421197:C:G	A114P	1.000
1:50421199:A:G	V113A	1.000
1:50421200:C:A	V113L	1.000
1:50421200:C:G	V113L	1.000
1:50421200:C:T	V113M	1.000

dbSNP variants (sampled 300 via entrez): RS1000251183 (1:50421771 G>A,T), RS1000429618 (1:50418014 TATAG>T), RS1000641211 (1:50421379 C>T), RS1000706353 (1:50422245 G>A), RS1000901871 (1:50422631 A>AC), RS1001233417 (1:50421011 T>A,C,G), RS1002521837 (1:50423819 C>T), RS1002638481 (1:50417375 T>C), RS1002759418 (1:50423569 G>A,T), RS1002958679 (1:50423944 C>G), RS1002971075 (1:50425439 C>T), RS1002996278 (1:50417113 C>G,T), RS1003476041 (1:50425276 A>G), RS1003527326 (1:50425238 C>G,T), RS1003593297 (1:50418650 G>C)

Disease associations

OMIM: gene MIM:614804 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Limited	Autosomal recessive

Mondo (1): (MONDO:0018393)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST005116_34	Male-pattern baldness	6.000000e-13
GCST005306_4	Atrial fibrillation	2.000000e-11
GCST006661_33	Male-pattern baldness	9.000000e-12
GCST006881_6	Hippocampal tail volume (corrected for total hippocampal volume)	4.000000e-10
GCST008971_22	Urate levels	2.000000e-07
GCST008972_207	Urate levels	2.000000e-09
GCST010696_17	Cortical thickness (min-P)	9.000000e-11
GCST010697_16	Cortical surface area (min-P)	5.000000e-09
GCST010698_74	Subcortical volume (min-P)	2.000000e-13
GCST010699_35	Brain morphology (min-P)	9.000000e-09
GCST010700_50	Cortical thickness (MOSTest)	2.000000e-10
GCST010701_119	Cortical surface area (MOSTest)	5.000000e-11
GCST010702_4	Subcortical volume (MOSTest)	3.000000e-08
GCST010703_110	Brain morphology (MOSTest)	6.000000e-20
GCST010989_169	Body size at age 10	9.000000e-10
GCST90013405_43	Liver enzyme levels (alanine transaminase)	8.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
aristolochic acid I	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	decreases methylation	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation	1
Ozone	increases oxidation, increases abundance, affects cotreatment	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1
Volatile Organic Compounds	increases oxidation, affects cotreatment	1

Clinical trials (associated diseases)

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