ATRAID

Summary

ATRAID (all-trans retinoic acid induced differentiation factor, HGNC:24090) is a protein-coding gene on chromosome 2p23.3, encoding All-trans retinoic acid-induced differentiation factor (Q6UW56). Promotes osteoblast cell differentiation and terminal mineralization.

This gene is thought to be involved in apoptosis, and may also be involved in hematopoietic development and differentiation. The use of alternative splice sites and promotors result in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 51374 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_001170795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24090
Approved symbol	ATRAID
Name	all-trans retinoic acid induced differentiation factor
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	HSPC013, p18, APR3
Ensembl gene	ENSG00000138085
Ensembl biotype	protein_coding
OMIM	619682
Entrez	51374

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000380171, ENST00000405489, ENST00000419744, ENST00000472515, ENST00000484646, ENST00000491220, ENST00000892973, ENST00000934372

RefSeq mRNA: 2 — MANE Select: NM_001170795 NM_001170795, NM_016085

CCDS: CCDS46243, CCDS62877

Canonical transcript exons

ENST00000380171 — 7 exons

Exon	Start	End
ENSE00000809105	27215321	27215392
ENSE00000809106	27215474	27215545
ENSE00000809107	27215632	27215753
ENSE00001382915	27216523	27216620
ENSE00001483998	27212041	27212467
ENSE00001936565	27216844	27217157
ENSE00003514421	27213177	27213298

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.1445 / max 338.7796, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19330	79.9546	1826
19329	16.0893	1810
19331	0.1007	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.11	gold quality
corpus epididymis	UBERON:0004359	98.77	gold quality
right uterine tube	UBERON:0001302	98.57	gold quality
adult organism	UBERON:0007023	98.44	gold quality
apex of heart	UBERON:0002098	98.23	gold quality
left ovary	UBERON:0002119	98.23	gold quality
right ovary	UBERON:0002118	98.17	gold quality
right atrium auricular region	UBERON:0006631	98.12	gold quality
left lobe of thyroid gland	UBERON:0001120	98.08	gold quality
right testis	UBERON:0004534	98.08	gold quality
right lobe of thyroid gland	UBERON:0001119	98.06	gold quality
cardiac atrium	UBERON:0002081	98.04	gold quality
parotid gland	UBERON:0001831	98.03	gold quality
nipple	UBERON:0002030	98.03	gold quality
left testis	UBERON:0004533	98.03	gold quality
endocervix	UBERON:0000458	98.02	gold quality
mucosa of stomach	UBERON:0001199	98.02	gold quality
right adrenal gland	UBERON:0001233	97.94	gold quality
right coronary artery	UBERON:0001625	97.93	gold quality
right adrenal gland cortex	UBERON:0035827	97.93	gold quality
thyroid gland	UBERON:0002046	97.88	gold quality
seminal vesicle	UBERON:0000998	97.86	gold quality
left adrenal gland cortex	UBERON:0035825	97.86	gold quality
body of uterus	UBERON:0009853	97.85	gold quality
nephron tubule	UBERON:0001231	97.80	gold quality
left adrenal gland	UBERON:0001234	97.78	gold quality
adrenal cortex	UBERON:0001235	97.78	gold quality
left uterine tube	UBERON:0001303	97.75	gold quality
heart	UBERON:0000948	97.74	gold quality
islet of Langerhans	UBERON:0000006	97.73	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	35.23
E-CURD-112	yes	5.87
E-MTAB-9689	no	391.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

15 targeting ATRAID, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-5000-5P	97.40	66.11	1055
HSA-MIR-4662A-3P	97.02	67.77	941
HSA-MIR-664B-5P	96.74	67.50	509

Literature-anchored findings (GeneRIF, showing 5)

• These data suggested that APR3 might be functionally important in certain processes under which NFAT and/or NFkappaB are/is activated. (PMID:17387583)
• the effects of NELL-1 on osteoblastic differentiation and proliferation are partly through binding to APR3 (PMID:21723284)
• APR3 expression is increased significantly with malignant progression of human cervical cervical squamous cell carcinoma (SCC), and thus, it may serve as a potential biomarker to predict prognosis of cervical SCC. (PMID:23036366)
• Nell-1 could reciprocally interact with APR3 and stimulate the differentiation and mineralization of human dental pulp cells. (PMID:31416616)
• The Genetics of Atypical Femur Fractures-a Systematic Review. (PMID:33587247)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	atraid	ENSDARG00000043388
mus_musculus	Atraid	ENSMUSG00000013622
rattus_norvegicus	Atraid	ENSRNOG00000087533

Protein

Protein identifiers

All-trans retinoic acid-induced differentiation factor — Q6UW56 (reviewed: Q6UW56)

Alternative names: Apoptosis-related protein 3, p18

All UniProt accessions (2): C9JA62, Q6UW56

UniProt curated annotations — full annotation on UniProt →

Function. Promotes osteoblast cell differentiation and terminal mineralization. Plays a role in inducing the cell cycle arrest via inhibiting CCND1 expression in all-trans-retinoic acid (ATRA) signal pathway. In osteoclasts, forms a transporter complex with ATRAID for nitrogen-containing-bisphophonates (N-BPs) required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol.

Subunit / interactions. Interacts with NELL1; the interaction promotes osteoblastic differentiation and mineralization. Interacts with SLC37A3; the interaction is direct and both proteins are mutually dependent for their stability.

Subcellular location. Nucleus envelope. Cell membrane. Lysosome membrane.

Tissue specificity. Weakly expressed in hematopoietic cell lines.

Induction. Up-regulated by all-trans-retinoic acid (ATRA) in several tumor cell lines.

Miscellaneous. Produced by alternative splicing of isoform 1. Produced by alternative promoter usage.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UW56-1	1	yes
Q6UW56-2	2
Q6UW56-3	3

RefSeq proteins (2): NP_001164266, NP_057169 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR042350	ATRAID	Family

UniProt features (20 total): sequence conflict 4, glycosylation site 4, disulfide bond 3, splice variant 2, topological domain 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UW56-F1	87.31	0.70

Functional residue map

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

Disulfide bonds (3): 156–171, 165–181, 183–192

Glycosylation sites (4): 44, 79, 157, 168

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 146 (showing top): GOCC_VACUOLAR_MEMBRANE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_XENOBIOTIC_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_BONE_MINERALIZATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_OSSIFICATION, GOBP_REGULATION_OF_OSTEOBLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_OSTEOBLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (7): xenobiotic transmembrane transport (GO:0006855), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154), positive regulation of bone mineralization (GO:0030501), negative regulation of osteoblast proliferation (GO:0033689), negative regulation of protein catabolic process (GO:0042177), positive regulation of osteoblast differentiation (GO:0045669)

GO Molecular Function (2): xenobiotic transmembrane transporter activity (GO:0042910), protein binding (GO:0005515)

GO Cellular Component (7): nuclear envelope (GO:0005635), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634), lysosome (GO:0005764), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
xenobiotic transport	2
cellular anatomical structure	2
transmembrane transport	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cellular developmental process	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
negative regulation of cell population proliferation	1
osteoblast proliferation	1
regulation of osteoblast proliferation	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
transmembrane transporter activity	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cytoplasm	1
intracellular membrane-bounded organelle	1
lytic vacuole	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATRAID	MAGEH1	Q9H213	871
ATRAID	SLC37A3	Q8NCC5	654
ATRAID	DDX54	Q8TDD1	573
ATRAID	FNDC4	Q9H6D8	557
ATRAID	EPS8	Q12929	464
ATRAID	EIF2B4	Q9UI10	462
ATRAID	SUMF2	Q8NBJ7	450
ATRAID	SNX17	Q15036	444
ATRAID	MXRA7	P84157	436
ATRAID	OSTM1	Q86WC4	412
ATRAID	ABHD1	Q96SE0	411
ATRAID	GGPS1	O95749	397
ATRAID	NELL1	Q92832	396
ATRAID	TMEM161B	Q8NDZ6	388
ATRAID	TECR	Q9NZ01	381

IntAct

18 interactions, top by confidence:

A	B	Type	Score
NFE2L2	KEAP1	psi-mi:“MI:0914”(association)	0.980
KEAP1	NFE2L2	psi-mi:“MI:0914”(association)	0.980
NELL1	ATRAID	psi-mi:“MI:0915”(physical association)	0.610
NELL1	ATRAID	psi-mi:“MI:0403”(colocalization)	0.610
SNX9	ATRAID	psi-mi:“MI:0915”(physical association)	0.520
ATRAID	SNX9	psi-mi:“MI:0915”(physical association)	0.520
CYP2D6	ATRAID	psi-mi:“MI:0915”(physical association)	0.400
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
SLC37A3	APOB	psi-mi:“MI:0914”(association)	0.350
KCNIP1	ATRAID	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
SLC37A3	PLXNB2	psi-mi:“MI:0914”(association)	0.350
SLC39A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATRAID	csbX	psi-mi:“MI:0915”(physical association)	0.000
ATRAID	LPP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): ATRAID (Affinity Capture-MS), ATRAID (Two-hybrid), ATRAID (Negative Genetic), ATRAID (Affinity Capture-Western), ATRAID (Affinity Capture-Western), ATRAID (Affinity Capture-MS), ATRAID (Affinity Capture-MS), ATRAID (Affinity Capture-MS), ATRAID (Affinity Capture-MS), SLC37A3 (Co-fractionation), PVR (Co-fractionation), BCAP29 (Co-fractionation), CD276 (Co-fractionation), ECI1 (Co-fractionation), EPB41 (Co-fractionation)

ESM2 similar proteins: A0A1B0GW64, A4FUY1, A5D7B2, A6QQ85, A8MVS5, B0FP48, E5RIL1, O18796, O19131, O75022, O75023, P09564, P0C191, P15151, P19438, P24071, P31994, P31995, P32506, P32942, P38484, P49772, P50555, Q01113, Q13477, Q14CZ8, Q28110, Q5DRQ8, Q61190, Q640R3, Q6AZ51, Q6BAA4, Q6GTX8, Q6PGD0, Q6UW56, Q6UX52, Q75VT8, Q7Z692, Q863H2, Q86YD3

Diamond homologs: A3KNS9, Q6PGD0, Q6UW56

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1055 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27212096:G:GT	donor_gain	1.0000
2:27212117:G:GT	donor_gain	1.0000
2:27212117:G:T	donor_gain	1.0000
2:27212161:G:GT	donor_gain	1.0000
2:27215393:G:GG	donor_gain	1.0000
2:27215546:G:GG	donor_gain	1.0000
2:27216513:T:TA	acceptor_gain	1.0000
2:27216522:GAAAT:G	acceptor_gain	1.0000
2:27212234:G:GT	donor_gain	0.9900
2:27212235:A:T	donor_gain	0.9900
2:27212292:G:T	donor_gain	0.9900
2:27213103:T:G	donor_gain	0.9900
2:27215315:CCTCA:C	acceptor_loss	0.9900
2:27215317:TCAG:T	acceptor_loss	0.9900
2:27215318:CAGG:C	acceptor_loss	0.9900
2:27215319:A:AG	acceptor_gain	0.9900
2:27215319:AGGCT:A	acceptor_gain	0.9900
2:27215320:G:C	acceptor_loss	0.9900
2:27215320:G:GG	acceptor_gain	0.9900
2:27215320:GGCT:G	acceptor_gain	0.9900
2:27215320:GGCTG:G	acceptor_gain	0.9900
2:27215374:C:T	donor_gain	0.9900
2:27215389:TCAT:T	donor_gain	0.9900
2:27215389:TCATG:T	donor_loss	0.9900
2:27215390:CAT:C	donor_gain	0.9900
2:27215390:CATG:C	donor_loss	0.9900
2:27215391:AT:A	donor_gain	0.9900
2:27215391:ATGTA:A	donor_loss	0.9900
2:27215392:TG:T	donor_loss	0.9900
2:27215393:GTA:G	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000109313 (2:27211259 C>G), RS1000424545 (2:27214891 A>G), RS1001449501 (2:27213931 C>A,G), RS1001834084 (2:27212611 C>T), RS1001935191 (2:27214548 T>G), RS1002367918 (2:27214228 G>C), RS1002748265 (2:27217329 C>G,T), RS1002969472 (2:27212929 G>A), RS1003084302 (2:27217136 T>C), RS1003473772 (2:27211323 G>A), RS1003859670 (2:27213012 C>G,T), RS1004427906 (2:27210118 A>T), RS1004649195 (2:27217350 C>T), RS1004680271 (2:27217439 C>A,G,T), RS1004785656 (2:27211756 C>A)

Disease associations

OMIM: gene MIM:619682 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Rotenone	increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
GSK-J4	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	increases expression	1
deguelin	increases expression	1
pyrimidifen	increases expression	1
ICG 001	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Aspirin	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SI	Abcam HEK293T ATRAID KO	Transformed cell line	Female

Clinical trials (associated diseases)

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