DAOA

Summary

DAOA (D-amino acid oxidase activator, HGNC:21191) is a protein-coding gene on chromosome 13q33.2, encoding D-amino acid oxidase regulator (P59103). May suppress DAO (D-amino acid oxidase) and SOD1 activity and promote their degradation.

This gene encodes a protein that may function as an activator of D-amino acid oxidase, which degrades the gliotransmitter D-serine, a potent activator of N-methyl-D-aspartate (NMDA) type glutamate receptors. Studies also suggest that one encoded isoform may play a role in mitochondrial function and dendritic arborization. Polymorphisms in this gene have been implicated in susceptibility to schizophrenia and bipolar affective disorder. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 267012 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 30 total
• Phenotypes (HPO): 7
• MANE Select transcript: NM_172370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21191
Approved symbol	DAOA
Name	D-amino acid oxidase activator
Location	13q33.2
Locus type	gene with protein product
Status	Approved
Aliases	G72
Ensembl gene	ENSG00000182346
Ensembl biotype	protein_coding
OMIM	607408
Entrez	267012

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 nonsense_mediated_decay, 4 protein_coding

ENST00000329625, ENST00000375936, ENST00000471432, ENST00000473269, ENST00000488534, ENST00000489237, ENST00000559369, ENST00000595812, ENST00000600388, ENST00000601240, ENST00000618629

RefSeq mRNA: 6 — MANE Select: NM_172370 NM_001161812, NM_001161814, NM_001384644, NM_001384645, NM_001384646, NM_172370

CCDS: CCDS41905, CCDS53880, CCDS59242, CCDS91834

Canonical transcript exons

ENST00000375936 — 6 exons

Exon	Start	End
ENSE00001468866	105490912	105491034
ENSE00001942959	105466216	105466332
ENSE00001943978	105466045	105466060
ENSE00003202160	105467053	105467141
ENSE00003479375	105472538	105472685
ENSE00003687593	105489901	105490192

Expression profiles

Bgee: expression breadth tissue_specific, 1 present calls, max score 56.91.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	56.91	gold quality
upper leg skin	UBERON:0004262	48.41	silver quality
lower lobe of lung	UBERON:0008949	45.13	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
inferior vagus X ganglion	UBERON:0005363	41.87	gold quality
cartilage tissue	UBERON:0002418	41.45	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
trigeminal ganglion	UBERON:0001675	41.20	gold quality
middle temporal gyrus	UBERON:0002771	41.20	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
myocardium	UBERON:0002349	40.45	gold quality
pigmented layer of retina	UBERON:0001782	40.44	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
mammary duct	UBERON:0001765	40.34	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality
oviduct epithelium	UBERON:0004804	40.03	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
deltoid	UBERON:0001476	39.83	gold quality
saphenous vein	UBERON:0007318	39.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting DAOA, 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-5582-3P	99.86	72.48	4221
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-6741-5P	93.86	63.06	437

Literature-anchored findings (GeneRIF, showing 40)

• The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia. (PMID:12364586)
• data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes (PMID:12647258)
• The association of variation at G72 with schizophrenia as well as bipolar disorder provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background (PMID:14966479)
• Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified. (PMID:15121480)
• identified statistically significant differences in allele distributions of two markers rs3916965 and rs2391191, and a highly significant association between haplotype AGAC of the G72/G30 locus and schizophrenia in the Chinese population (PMID:15194506)
• G72 gene analysis was dominated by under-transmissions. Negative transmissions involved a core haplotype complementary to the originally detected over-transmitted haplotype, suggesting the presence of a protective variant within the G72 locus. (PMID:15248869)
• the G72 region is involved in susceptibility to schizophrenia in the Ashkenazi population. (PMID:15271585)
• Results suggest that variability of the DAOA/G30 locus may be involved in the etiology of panic disorder. (PMID:15477870)
• Identifies LTR class mobile element sequences at the G72/G30 locus. (PMID:15546984)
• This study failed to find evidence for an association for schizophrenia with single nucleotide polymorphisms at the G72/G30 locus. (PMID:15738936)
• A statistically significant association was found between rs778293 and schizophrenia in Asian populations, but not European populations. (PMID:16402132)
• SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia (PMID:16554747)
• The G72/G30 gene may be implicated in susceptibility to schizophrenia and there may be an interaction between this gene and sex in the pathogenesis of schizophrenia. (PMID:16791105)
• SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. (PMID:17006672)
• The G72 gene polymorphism may be associated with female depressive patients without mixed family history,C allele of rs947267 may be the risk factor. (PMID:17029202)
• The results suggest that there is weak evidence of association between the G72/G30 genes and schizophrenia. (PMID:17179078)
• These findings suggest that the G72/G30 gene may modulate the age at onset and there might be a potential interaction between this locus and sex in the pathogenesis of schizophrenia. (PMID:17179866)
• The genes G72 is regulate the glutamate neurotransmission in schizophrenia. (PMID:17250995)
• results support the hypothesis that variations in DAOA may play a role in schizophrenia and clinical characteristics (PMID:17293043)
• association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland (PMID:17492767)
• Data suggest that the D-amino acid oxidase activator (DAOA/G30) locus, but not D-amino acid oxidase, may play a role in the pathophysiology of schizophrenia. (PMID:17627036)
• genetic associations between the DAOA gene and autism spectrum disorders (PMID:17629951)
• Association of polymorphism with schizophrenia not consistent with those found in other populations, and may be chance findings. (PMID:17651942)
• failure to confirm originally proposed functional interaction between G72 and D-amino acid oxidase (DAO) in two tested cell lines implicating a candidate schizophrenia/bipolar disorder susceptibility gene. (PMID:17684499)
• Polymorphisms are not associated with homicidal behavior in korean schizophrenics. (PMID:17728673)
• The DAOA ARG30LYS is significant association with poor memory performance in schizophrenia. (PMID:17767147)
• serine racemase and D-amino acid oxidase are expressed in human brain and demonstrate aberrant D-serine metabolism in schizophrenia (PMID:17880399)
• These results suggest that G72/G30 may influence susceptibility to schizophrenia with weak effects. (PMID:18023149)
• Some support for the individual involvement of DAO and G72(DAOA)/G30 in the etiology of bipolar disorder. (PMID:18165970)
• This is the first study to the authors’ knowledge to implicate the G72 locus in the etiology of major depression and neuroticism. (PMID:18346999)
• These results support the view that genetic variation in the DAOA gene influences hippocampal complex and prefrontal cortex function, an effect that might be particularly prominent in the context of enhanced genetic risk for schizophrenia. (PMID:18423426)
• The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits. (PMID:18466879)
• Data show that the specific alleles in the genes for DAOA (G72/G30) reveal associations for each of both affective and schizophrenic disorders in the same direction in some. (PMID:18516516)
• We report a significant effect of DAOA variation on risk for schizophrenia. (PMID:18541412)
• a decrease in the synaptic concentration of d-serine as the result of an anomalous increase in hDAAO activity related to hypoexpression of pLG72 may represent a molecular mechanism by which hDAAO and pLG72 are involved in schizophrenia susceptibility (PMID:18544534)
• The G72/G30 complex is considered as one of the most promising candidate genes for both schizophrenia and bipolar disorder. (PMID:18775646)
• Lack of demonstrable G72 expression in relevant brain regions does not support a role for G72 in modulation of DAO activity and the pathology of schizophrenia via a DAO-mediated mechanism. (PMID:19077230)
• DAOA is identified as a potential contributor to juvenile-onset mood disorders. (PMID:19089835)
• high risk variant of the G72 vulnerability gene for schizophrenia does not necessarily have to negatively affect cognitive abilities (PMID:19167508)
• The transgenic mice which expression of the human G72/G30 gene locus in mice produces behavioral phenotypes that are relevant to psychiatric disorders. (PMID:19189879)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

D-amino acid oxidase regulator — P59103 (reviewed: P59103)

Alternative names: Protein G72

All UniProt accessions (6): P59103, A2T115, M0R0L0, M0R2M6, M0R2W9, Q8IWM3

UniProt curated annotations — full annotation on UniProt →

Function. May suppress DAO (D-amino acid oxidase) and SOD1 activity and promote their degradation. Has conversely also been suggested to function as a DAO activator. May stimulate the degradation of DDO (D-aspartate oxidase). May play a role in mitochondrial fission.

Subunit / interactions. Interacts with DAO (D-amino acid oxidase); the interaction is direct, can occur in the presence or absence of FAD or substrate bound to DAO, and results in a complex containing two DAO homodimers and two DAOA monomers. Interacts with DDO (D-aspartate oxidase); the interaction is direct. Interacts wih SOD1; the interaction is direct. Interacts with MSRB2; the interaction is direct.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus. Mitochondrion.

Tissue specificity. Expressed in the amygdala and in astrocytes of the cortex (at protein level). Expressed in the caudate nucleus, spinal cord and testis.

Disease relevance. Schizophrenia (SCZD) [MIM:181500] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (4)

UniProt ID	Names	Canonical?
P59103-1	1, LG72	yes
P59103-2	2, SG72
P59103-3	3
P59103-4	4

RefSeq proteins (6): NP_001155284, NP_001155286, NP_001371573, NP_001371574, NP_001371575, NP_758958* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027929	DAOA	Family

Pfam: PF15199

UniProt features (9 total): splice variant 4, region of interest 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P59103-F1	46.78	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 41 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, ZNF274_TARGET_GENES, MIR4505, MIR5787, MIR6842_3P, HP_HALLUCINATIONS

GO Biological Process (2): positive regulation of protein catabolic process (GO:0045732), D-amino acid metabolic process (GO:0046416)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
non-proteinogenic amino acid metabolic process	1
binding	1
endomembrane system	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DAOA	DAO	P14920	983
DAOA	DTNBP1	Q96EV8	866
DAOA	DISC1	Q9NRI5	820
DAOA	ZNF804A	Q7Z570	762
DAOA	COMT	P21964	745
DAOA	RGS4	P49798	732
DAOA	PPP3CC	P48454	687
DAOA	TAAR6	Q96RI8	685
DAOA	PRODH	O43272	651
DAOA	DRD4	P21917	649
DAOA	ZDHHC8	Q9ULC8	645
DAOA	HTR2A	P28223	637
DAOA	PRODH	O43272	628
DAOA	GABRB2	P47870	608
DAOA	NOS1AP	O75052	605

IntAct

3 interactions, top by confidence:

A	B	Type	Score
Dao	DAOA	psi-mi:“MI:0407”(direct interaction)	0.440
DAOA	DDAH2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (7): DAOA (Far Western), DAOA (Far Western), DAOA (Co-purification), DAOA (Co-purification), DAO (Reconstituted Complex), DAOA (Negative Genetic), DDAH2 (Affinity Capture-MS)

ESM2 similar proteins: A3KGA4, A4QNW7, A6H7E2, A6NKT7, B1WBT0, C9JQI7, F4JUI3, O04407, O14715, O74982, O94293, P0C137, P0C139, P0C142, P0DJD0, P0DJD1, P33493, P52473, P52546, P59103, Q01640, Q02872, Q05323, Q0P4L7, Q0VD34, Q3SZQ3, Q568Z9, Q5K6N0, Q5MKM1, Q5R4I8, Q67402, Q6NVG5, Q6P566, Q6WB97, Q77DJ5, Q7TD12, Q7Z3J3, Q8BGD0, Q8IR45, Q8K0S0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

643 predictions. Top by Δscore:

Variant	Effect	Δscore
13:105466330:CAGG:C	donor_loss	1.0000
13:105466331:AGGTA:A	donor_loss	1.0000
13:105466333:G:GG	donor_gain	0.9900
13:105472684:GA:G	donor_gain	0.9900
13:105466331:AGGT:A	donor_gain	0.9800
13:105472686:G:GG	donor_gain	0.9800
13:105489899:A:AG	acceptor_gain	0.9800
13:105489900:G:GG	acceptor_gain	0.9800
13:105466330:CAGGT:C	donor_gain	0.9700
13:105467138:ATTGG:A	donor_loss	0.9700
13:105467140:TGG:T	donor_loss	0.9700
13:105467141:GGTAT:G	donor_loss	0.9700
13:105467142:G:GG	donor_gain	0.9700
13:105467142:GTATG:G	donor_loss	0.9700
13:105467143:T:A	donor_loss	0.9700
13:105489895:TTACA:T	acceptor_loss	0.9700
13:105489896:TACAG:T	acceptor_loss	0.9700
13:105489897:ACAGG:A	acceptor_loss	0.9700
13:105489898:CA:C	acceptor_loss	0.9700
13:105489899:A:AT	acceptor_loss	0.9700
13:105472681:GCAGA:G	donor_gain	0.9600
13:105489891:CTCCT:C	acceptor_loss	0.9600
13:105489892:TCCTT:T	acceptor_loss	0.9600
13:105489893:CCTTA:C	acceptor_loss	0.9600
13:105489894:CTTA:C	acceptor_loss	0.9600
13:105489900:GGCTT:G	acceptor_gain	0.9600
13:105466331:AG:A	donor_gain	0.9400
13:105466332:GG:G	donor_gain	0.9400
13:105467050:TAGA:T	acceptor_gain	0.9400
13:105467051:AGATC:A	acceptor_gain	0.9300

AlphaMissense

1007 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:105467090:T:C	F28L	0.946
13:105467092:T:A	F28L	0.946
13:105467092:T:G	F28L	0.946
13:105490009:G:C	W130C	0.935
13:105490009:G:T	W130C	0.935
13:105490007:T:A	W130R	0.931
13:105490007:T:C	W130R	0.931
13:105466328:T:C	F14L	0.905
13:105466330:C:A	F14L	0.905
13:105466330:C:G	F14L	0.905
13:105472634:T:C	L77S	0.848
13:105472587:G:C	W61C	0.839
13:105472587:G:T	W61C	0.839
13:105467081:T:C	F25L	0.837
13:105467083:C:A	F25L	0.837
13:105467083:C:G	F25L	0.837
13:105490008:G:C	W130S	0.830
13:105489956:T:C	F113L	0.808
13:105489958:C:A	F113L	0.808
13:105489958:C:G	F113L	0.808
13:105490033:A:C	K138N	0.786
13:105490033:A:T	K138N	0.786
13:105467091:T:C	F28S	0.781
13:105472585:T:A	W61R	0.776
13:105472585:T:C	W61R	0.776
13:105472590:G:C	K62N	0.775
13:105472590:G:T	K62N	0.775
13:105467070:G:A	G21D	0.770
13:105490030:A:C	Q137H	0.769
13:105490030:A:T	Q137H	0.769

dbSNP variants (sampled 300 via entrez): RS1000147002 (13:105467587 T>C,G), RS1000321049 (13:105469228 T>C), RS1000322852 (13:105463919 T>C), RS1000492489 (13:105484670 C>T), RS1000554169 (13:105469278 T>C,G), RS1000608842 (13:105464849 T>C), RS1000902824 (13:105489392 C>T), RS1000908597 (13:105490282 A>G), RS1000939317 (13:105490000 A>G), RS1001068583 (13:105484321 T>G), RS1001185498 (13:105474269 C>T), RS1001225307 (13:105475862 T>C), RS1001269969 (13:105469652 C>T), RS1001271443 (13:105489116 A>C,T), RS1001342153 (13:105469932 T>A,C)

Disease associations

OMIM: gene MIM:607408 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000738	Hallucinations
HP:0000746	Delusion
HP:0002353	EEG abnormality
HP:0007086	Social and occupational deterioration
HP:0100753	Schizophrenia
HP:0410291	Negativism

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000821_59	Bipolar disorder and schizophrenia	1.000000e-07
GCST001525_26	Visceral fat	9.000000e-06
GCST001762_170	Obesity-related traits	3.000000e-06
GCST001762_748	Obesity-related traits	4.000000e-06
GCST002129_2	Periodontitis (DPAL)	7.000000e-06
GCST002491_20	Age-related hearing impairment	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs778293	Toxicity	3	methamphetamine	Psychotic Disorder

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs778293	DAOA	3	2.75	1	methamphetamine
rs947267	DAOA, DAOA-AS1		0.00	0
rs2391191	DAOA, DAOA-AS1		0.00	0
rs3916965	DAOA		0.00	0

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Folic Acid	decreases expression	1
Lead	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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