AIRE

Summary

AIRE (autoimmune regulator, HGNC:360) is a protein-coding gene on chromosome 21q22.3, encoding Autoimmune regulator (O43918). Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antige….

This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED).

Source: NCBI Gene 326 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoimmune polyendocrine syndrome type 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 1,348 total — 108 pathogenic, 93 likely-pathogenic
• Phenotypes (HPO): 82
• Transcription factor: yes — 24 downstream targets (CollecTRI)
• MANE Select transcript: NM_000383

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:360
Approved symbol	AIRE
Name	autoimmune regulator
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PGA1, APS1
Ensembl gene	ENSG00000160224
Ensembl biotype	protein_coding
OMIM	607358
Entrez	326

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 retained_intron, 2 protein_coding

ENST00000291582, ENST00000337909, ENST00000397994, ENST00000527919, ENST00000530812, ENST00000966178

RefSeq mRNA: 1 — MANE Select: NM_000383 NM_000383

CCDS: CCDS13706

Canonical transcript exons

ENST00000291582 — 14 exons

Exon	Start	End
ENSE00001050710	44285876	44286138
ENSE00001050714	44286978	44287133
ENSE00001050716	44287517	44287591
ENSE00001136688	44291095	44291210
ENSE00003484440	44286557	44286731
ENSE00003524824	44288345	44288458
ENSE00003560932	44292302	44292401
ENSE00003569099	44292993	44293175
ENSE00003586834	44296383	44296445
ENSE00003592619	44289657	44289802
ENSE00003600226	44293789	44293910
ENSE00003664932	44294401	44294503
ENSE00003668332	44297656	44298648
ENSE00003685344	44289988	44290068

Expression profiles

Bgee: expression breadth ubiquitous, 105 present calls, max score 79.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2230 / max 235.4658, expressed in 34 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189456	0.1804	22
189455	0.0210	3
189454	0.0137	4
189453	0.0080	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
triceps brachii	UBERON:0001509	79.58	gold quality
diaphragm	UBERON:0001103	78.56	gold quality
gluteal muscle	UBERON:0002000	78.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.23	gold quality
olfactory bulb	UBERON:0002264	71.71	gold quality
tongue squamous epithelium	UBERON:0006919	70.75	gold quality
male germ cell	CL:0000015	70.42	gold quality
sperm	CL:0000019	70.18	gold quality
type B pancreatic cell	CL:0000169	69.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	68.32	gold quality
parotid gland	UBERON:0001831	67.84	gold quality
hypothalamus	UBERON:0001898	67.78	gold quality
vastus lateralis	UBERON:0001379	67.23	gold quality
quadriceps femoris	UBERON:0001377	66.84	gold quality
decidua	UBERON:0002450	65.46	gold quality
buccal mucosa cell	CL:0002336	65.15	gold quality
biceps brachii	UBERON:0001507	63.66	gold quality
heart right ventricle	UBERON:0002080	63.44	gold quality
upper arm skin	UBERON:0004263	63.30	gold quality
cingulate cortex	UBERON:0003027	63.17	gold quality
anterior cingulate cortex	UBERON:0009835	62.86	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.69	gold quality
mucosa of urinary bladder	UBERON:0001259	62.58	gold quality
lymph node	UBERON:0000029	61.83	gold quality
epithelial cell of pancreas	CL:0000083	61.42	gold quality
granulocyte	CL:0000094	60.78	gold quality
skeletal muscle tissue	UBERON:0001134	60.72	gold quality
secondary oocyte	CL:0000655	60.58	gold quality
orbitofrontal cortex	UBERON:0004167	60.50	gold quality
deltoid	UBERON:0001476	60.00	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	716.30
E-ANND-3	no	1.94

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

24 targets.

Target	Regulation
AIRE
BMP2
CD28
CHRNA1	Unknown
COL2A1	Unknown
CREBBP
CSTB
CXCL8
CYP2A13	Activation
F11
FOS	Activation
ICA1	Repression
IFNB1	Unknown
IL2RA
INS
MUC6
NFKBIA
PIAS1
RAC1	Activation
TG	Activation
TLR3	Activation
TLR8
TSHR	Activation
TSPOAP1

Upstream regulators (CollecTRI, top): AIRE, DAXX, NFKB2

miRNA regulators (miRDB)

18 targeting AIRE, 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-4673	100.00	66.64	1490
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-4639-3P	97.54	67.12	787
HSA-MIR-10398-5P	97.12	64.94	1051

Literature-anchored findings (GeneRIF, showing 40)

• Expression of AIRE gene in peripheral monocyte/dendritic cell lineage (PMID:11803052)
• AIRE mutations as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. (PMID:12050215)
• The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. (PMID:12542742)
• The AIRE gene was analyzed in a 39-year old female with autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). Direct sequencing revealed a novel missense mutation at exon 1 (R15C) (PMID:12625412)
• characterization of regulatory elements and methylation pattern of promoter (PMID:12651856)
• disease-causing missense mutations in the PHD1 plant homeodomain (C311Y and P326Q) abolished its E3 ligase activity (PMID:14734522)
• results suggest that the transcriptional regulating activities of Autoimmune regulator (AIRE) within a cell are controlled and organized in a spatiotemporal ma (PMID:15150263)
• The 545-amino acid protein that is encoded by AIRE contains several structural motifs that are suggestive of a transcriptional regulator. (PMID:15157567)
• identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells (PMID:15482854)
• Results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development. (PMID:15696198)
• 2 novel mutations, c.230T>C (p.F77S) & c.64_69del (p.V22_D23del) within the HSR domain were found in autoimmune polyendocrinopathy-candidasis ectodermal dystrophy. Both negatively affected homodimerization. (PMID:15712268)
• Three novel AIRE gene mutations were identified (PMID:15886230)
• AIRE gene expression is regulated by mitogen-activated protein kinase pathway (PMID:15894121)
• AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP (PMID:15964547)
• Our results indicate that the c.682T>G (p.G228W) mutant AIRE protein acts with a dominant negative effect by binding to the wild-type AIRE, thus preventing the protein from forming the complexes needed for transactivation. (PMID:16114041)
• Levels of autoimmune transcription regulator AIRE expression in the thymus may exert a stronger influence than does the expression of the insulin gene IDDM2 alleles themselves. (PMID:16246524)
• AIRE regulates gene expression by recruiting components of the transcription complex to specific regions of the genome via interactions with nuclear matrix. (PMID:16310047)
• The AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population. (PMID:16552513)
• The study results do not support the hypothesis that the p.SER278Arg polymorphism of the AIRE gene is associated with an increased risk for alopecia areata. (PMID:16774540)
• Ets transcription factor family members Ets-1, Ets-2, and ESE-1 have positive effect on AIRE transcription. (PMID:16890195)
• six new mutations were identified in the Norwegian APS I patients (PMID:17118990)
• We saw a significant amount of non-endocrine disease but no ectodermal dystrophy. AIRE gene analysis reassured many siblings and identified individuals with APECED prior to any symptoms. (PMID:17220063)
• Review discusses the expression of AIRE in medullary thymus epithelial cells and its control of promiscuous expression of sets of self antigens. (PMID:17323409)
• a new transactivation domain of the AIRE protein localized in the COOH terminal region (PMID:17675238)
• findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity (PMID:17687331)
• sequence in promoter differentially methylated between peripheral blood and placental tissue (PMID:17697502)
• genetic variation in AIRE does not appear to play a role in vitiligo-associated multiple autoimmune disease (PMID:17850514)
• study describes three patients with rare thymoma-related autoimmune graft-versus-host-like disease and shows that the neoplastic compartment of their thymomas lack expression of AIRE (PMID:17928069)
• These findings reveal critical steps by which AIRE regulates the transcription of genes that control central tolerance in the thymus. (PMID:17938200)
• Combined homology modeling and in vitro data now show how APECED mutations influence the activity of this transcriptional regulator. (PMID:17974569)
• phosphorylation of the AIRE protein at Thr68 and Ser156 by DNA-Dependent Protein Kinase influences AIRE transactivation ability and might have impact on other aspects of the functional regulation of the AIRE protein (PMID:17997173)
• These data suggest that AIRE and PIAS1 interact functionally to regulate the activities of the target genes of AIRE. (PMID:18083234)
• AIRE risk haplotypes identified in this study potentially account for a major component of the genetic risk of developing alopecia areata. (PMID:18194361)
• Analysis of AIRE protein single nucleotide polymorphisms in autoimmune Addison’s disease and autoimmune polyendocrine syndrome type II finds that the AIRE gene is not associated with either disease. (PMID:18200029)
• The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. (PMID:18292755)
• First case study in the literature reports on the possibility of the Ala58Glycine mutation being associated with polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). (PMID:18320920)
• expressed in thymus B cells and CD4+CD8+ cells at a low level and in peripheral blood B cells and CD14+ dendritic cells (DCs)/macrophages and granulocytes at higher levels. AIRE mRNA was expressed higher in B cells than in T cells. (PMID:18324482)
• Our cases represent the first report of an association between APECED and CIDP, in which peripheral nerve demyelination may represent a novel disease component in APECED. (PMID:18461357)
• The infrequent and low expression of AIRE mRNA may play a role the induction of autoimmune diseases but other factors also seem to be involved (PMID:18568643)
• Data support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans. (PMID:18600308)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aire	ENSDARG00000056784
mus_musculus	Aire	ENSMUSG00000000731
rattus_norvegicus	Aire	ENSRNOG00000001213

Paralogs (5): ZMYND11 (ENSG00000015171), PHF21B (ENSG00000056487), ZMYND8 (ENSG00000101040), PHF12 (ENSG00000109118), PHF21A (ENSG00000135365)

Protein

Protein identifiers

Autoimmune regulator — O43918 (reviewed: O43918)

Alternative names: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein

All UniProt accessions (1): O43918

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA). Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5’-ATTGGTTA-3’ combined with a 5’-TTATTA-3’ box. Binds to nucleosomes. Binds to chromatin and interacts selectively with histone H3 that is not methylated at ‘Lys-4’, not phosphorylated at ‘Thr-3’ and not methylated at ‘Arg-2’. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Mainly expressed by medullary thymic epithelial cells (mTECs), induces the expression of thousands of tissue-restricted proteins, which are presented on major histocompatibility complex class I (MHC-I) and MHC-II molecules to developing T-cells percolating through the thymic medulla. Also induces self-tolerance through other mechanisms such as the regulation of the mTEC differentiation program. Controls the medullary accumulation of thymic dendritic cells and the development of regulatory T-cell through the regulation of XCL1 expression. Regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes. In thimic B-cells, allows the presentation of licensing-dependent endogenous self-anitgen for negative selection. In secondary lymphoid organs, induces functional inactivation of CD4(+) T-cells. Expressed by a distinct bone marrow-derived population, induces self-tolerance through a mechanism that does not require regulatory T-cells and is resitant to innate inflammatory stimuli.

Subunit / interactions. Homodimer and homotetramer. Interacts with CREBBP. Interacts preferentially with histone H3 that is not methylated at ‘Lys-4’. Binds with lower affinity to histone H3 that is monomethylated at ‘Lys-4’. Trimethylation of histone H3 at ‘Lys-4’ or phosphorylation at ‘Thr-3’ abolish the interaction. Binds with lower affinity to histone H3 that is acetylated at ‘Lys-4’, or that is acetylated at ‘Lys-9’ or trimethylated at ‘Lys-9’. Binds histone H3 that is dimethylated at ‘Arg-2’ with very low affinity.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. In secondary lymphoid organs, expressed in a discrete population of bone marrow-derived toleregenic antigen presenting cells (APCs) called extrathymic AIRE expressing cells (eTAC)(at protein level). Isoform 2 and isoform 3 seem to be less frequently expressed than isoform 1, if at all.

Post-translational modifications. Phosphorylated. Phosphorylation could trigger oligomerization.

Disease relevance. Autoimmune polyendocrine syndrome 1, with or without reversible metaphyseal dysplasia (APS1) [MIM:240300] A rare disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism. The disease is caused by variants affecting the gene represented in this entry. Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes. Heterozygous mutations within the PHD1 domain have dominant-negative effects and cause organ-specific autoimmune diseases. Patients harbor extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines such as type I interferons which could protect them from some types of autoimmune diseases, like type I diabetes.

Domain organisation. The L-X-X-L-L repeats may be implicated in binding to nuclear receptors. The HSR domain is required for localization on tubular structures (N-terminal part) and for homodimerization. Interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at ‘Lys-4’. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function.

Isoforms (4)

UniProt ID	Names	Canonical?
O43918-1	1, AIRE-1	yes
O43918-2	2, AIRE-2
O43918-3	3, AIRE-3
O43918-4	4

RefSeq proteins (1): NP_000374* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000770	SAND_dom	Domain
IPR001965	Znf_PHD	Domain
IPR004865	HSR_dom	Domain
IPR008087	AIRE	Family
IPR010919	SAND-like_dom_sf	Homologous_superfamily
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR042580	AIRE_PHD2	Domain
IPR043563	Sp110/Sp140/Sp140L-like	Family

Pfam: PF00628, PF01342, PF03172

UniProt features (88 total): sequence variant 37, mutagenesis site 14, region of interest 7, strand 7, turn 5, short sequence motif 4, compositionally biased region 3, splice variant 3, domain 2, zinc finger region 2, helix 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1XWH	SOLUTION NMR
2KE1	SOLUTION NMR
2KFT	SOLUTION NMR
2LRI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43918-F1	62.30	0.24

Functional residue map

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

Mutagenesis-validated functional residues (14):

Position	Phenotype
28–29	loss of doted nuclear location, forms nuclear smears. loss of transactivation activity on target genes transcription.
97	loss of transactivation activity on target gene transcription; no dominant-negative effect on target gene transcription.
295	abolishes interaction with histone h3.
297	strongly reduces interaction with unmethylated histone h3 and abolishes interaction with histone h3 trimethylated at ’ly
298	reduces interaction with histone h3.
302	reduces transcriptional activation.
303	alters protein folding and abolishes interaction with histone h3. no effect on doted nuclear localization. dominant-nega
304	strongly reduces interaction with histone h3.
307	reduces interaction with histone h3.
312	abolishes interaction with histone h3.
312	no effect on doted nuclear localization. dominant-negative effect on target gene transcription.
437	reduces transcription activation.
446	dominant-negative effect on regulation of target gene transcription.
471	no effect on regulation of target gene transcription.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 305 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_TOLERANCE_INDUCTION, GOBP_THYMIC_T_CELL_SELECTION, GOBP_THYMUS_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, CCATCCA_MIR432, GOBP_TRANSLATION, GOBP_REGULATION_OF_MONONUCLEAR_CELL_MIGRATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOMF_TRANSLATION_REGULATOR_ACTIVITY, GOBP_LEUKOCYTE_MIGRATION, MODULE_75

GO Biological Process (14): peripheral T cell tolerance induction (GO:0002458), central tolerance induction to self antigen (GO:0002509), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), immune response (GO:0006955), humoral immune response (GO:0006959), positive regulation of chemokine production (GO:0032722), negative thymic T cell selection (GO:0045060), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), thymus epithelium morphogenesis (GO:0097536), regulation of thymocyte migration (GO:2000410), tolerance induction (GO:0002507), regulation of translation (GO:0006417)

GO Molecular Function (9): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone binding (GO:0042393), identical protein binding (GO:0042802), translation regulator activity (GO:0045182), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): male germ cell nucleus (GO:0001673), female germ cell nucleus (GO:0001674), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear body (GO:0016604)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
immune system process	2
binding	2
protein binding	2
germ cell nucleus	2
T cell mediated immunity	1
peripheral tolerance induction	1
T cell tolerance induction	1
central tolerance induction	1
tolerance induction to self antigen	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
response to stimulus	1
immune response	1
positive regulation of cytokine production	1
chemokine production	1
regulation of chemokine production	1
negative T cell selection	1
thymic T cell selection	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
morphogenesis of an epithelium	1
thymus development	1
thymocyte migration	1
regulation of T cell migration	1
immune system development	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
transcription cis-regulatory region binding	1
transition metal ion binding	1
molecular_function	1
regulation of translation	1
nucleic acid binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2807 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIRE	EGLN2	Q96KS0	867
AIRE	NUDT10	Q8NFP7	833
AIRE	H3-7	Q5TEC6	818
AIRE	H3C1	P02295	817
AIRE	H3-4	Q16695	817
AIRE	H3-5	Q6NXT2	817
AIRE	H3C14	Q71DI3	817
AIRE	H3-3A	P06351	816
AIRE	NLRP5	P59047	781
AIRE	LTBR	P36941	768
AIRE	CHRNA1	P02708	764
AIRE	SLC7A9	P82251	743
AIRE	FOXN1	O15353	735
AIRE	CARD9	Q9H257	714
AIRE	CYP1A2	P05177	687

IntAct

59 interactions, top by confidence:

A	B	Type	Score
H3C1	AIRE	psi-mi:“MI:0915”(physical association)	0.690
H3C1	AIRE	psi-mi:“MI:0407”(direct interaction)	0.690
AIRE	H3C1	psi-mi:“MI:0407”(direct interaction)	0.690
AIRE	AIRE	psi-mi:“MI:0915”(physical association)	0.680
AIRE	DAXX	psi-mi:“MI:0915”(physical association)	0.540
DAXX	AIRE	psi-mi:“MI:0915”(physical association)	0.540
AIRE	DAXX	psi-mi:“MI:0403”(colocalization)	0.540
AIRE	ALOX12B	psi-mi:“MI:0914”(association)	0.530
PRKDC	AIRE	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (135): AIRE (Two-hybrid), GCN1L1 (Affinity Capture-MS), TMPO (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), FBXO3 (Affinity Capture-MS), DDX5 (Affinity Capture-MS), HNRNPF (Affinity Capture-MS), SMC3 (Affinity Capture-MS), SF3B3 (Affinity Capture-MS), TARDBP (Affinity Capture-MS), LANCL2 (Affinity Capture-MS), ATR (Affinity Capture-MS), FBXO3 (Affinity Capture-Western), CUL1 (Affinity Capture-Western), RBX1 (Affinity Capture-Western)

ESM2 similar proteins: A0JNJ4, A2APT9, A6NEL2, A6NP61, B1ASB6, B1WBS3, B2RXF5, F6WEQ6, O15015, O43918, O88282, O88286, O95785, P98168, P98169, Q2M3G4, Q2MHN3, Q2QGD7, Q3U1J1, Q3U381, Q497V6, Q5SW24, Q5SXM2, Q6YND2, Q6ZMQ8, Q6ZMY3, Q7TN08, Q7TSX9, Q80SU3, Q80YE4, Q811H0, Q8BG26, Q8BZW2, Q8C8V1, Q8IX07, Q8IY92, Q8N143, Q8N1G0, Q8NC74, Q8TBE0

Diamond homologs: A0A1W2PPD8, A1A5Q5, A1YVX4, A2A8L1, A2AUY4, A2BIL7, A6H619, A8DZJ1, A9LMC0, B2RXH2, B7ZS37, B9RU15, C0SUT9, D3ZD32, F4I240, F4I6G4, F4KIX0, O16102, O43918, O64752, O75164, O88379, O94953, O97159, P29375, P39956, P41228, P41229, P41230, P56163, P58268, P58269, P58270, Q03833, Q09477, Q10RP4, Q12873, Q14839, Q22516, Q23541

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DAXX	“down-regulates activity”	AIRE	binding
AIRE	“down-regulates quantity by repression”	ICA1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
Downstream signal transduction	6	91.4×	2e-08
FCGR3A-mediated phagocytosis	6	44.9×	7e-07
VEGFA-VEGFR2 Pathway	5	27.9×	5e-05
HCMV Early Events	5	16.2×	2e-04
Estrogen-dependent gene expression	5	15.1×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	68.8×	4e-06
DNA damage response	5	10.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1348 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	93
Uncertain significance	433
Likely benign	555
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069340	NC_000021.8:g.(?45705880)(45707026_?)del	Pathogenic
1069666	NM_000383.4(AIRE):c.347del (p.Pro116fs)	Pathogenic
1071086	NM_000383.4(AIRE):c.1182C>A (p.Tyr394Ter)	Pathogenic
1071371	NC_000021.8:g.(?45705870)(45707494_?)del	Pathogenic
1071372	NC_000021.8:g.(?45705870)(45711113_?)del	Pathogenic
1074719	NM_000383.4(AIRE):c.560C>G (p.Ser187Ter)	Pathogenic
1075365	NM_000383.4(AIRE):c.489del (p.Lys164fs)	Pathogenic
1075834	NM_000383.4(AIRE):c.784C>T (p.Gln262Ter)	Pathogenic
1076320	NM_000383.4(AIRE):c.747del (p.Ser249fs)	Pathogenic
1076711	NM_000383.4(AIRE):c.1192_1196dup (p.Pro400fs)	Pathogenic
1322985	NM_000383.4(AIRE):c.2T>A (p.Met1Lys)	Pathogenic
1361985	NM_000383.4(AIRE):c.599dup (p.Ala202fs)	Pathogenic
1401394	NM_000383.4(AIRE):c.1259_1260del (p.Val420fs)	Pathogenic
1415983	NM_000383.4(AIRE):c.36del (p.Arg12fs)	Pathogenic
1430725	NM_000383.4(AIRE):c.1143_1144del (p.Glu383fs)	Pathogenic
1441280	NM_000383.4(AIRE):c.1429G>T (p.Gly477Ter)	Pathogenic
1451244	NM_000383.4(AIRE):c.2T>G (p.Met1Arg)	Pathogenic
1454525	NM_000383.4(AIRE):c.969_975del (p.Ser324fs)	Pathogenic
1454596	NM_000383.4(AIRE):c.205C>T (p.Gln69Ter)	Pathogenic
1455222	NM_000383.4(AIRE):c.1214del (p.Pro405fs)	Pathogenic
1456179	NM_000383.4(AIRE):c.1250_1251insTCTCCTCGGCCCTGCACCCCCT (p.Cys419fs)	Pathogenic
1456925	NM_000383.4(AIRE):c.193_197dup (p.Leu67fs)	Pathogenic
1458364	NM_000383.4(AIRE):c.340A>T (p.Lys114Ter)	Pathogenic
1458570	NM_000383.4(AIRE):c.14_15del (p.Ala5fs)	Pathogenic
1522763	NM_000383.4(AIRE):c.253_255del (p.Tyr85del)	Pathogenic
1693557	NM_000383.3:c.995+(3_5)delGAGinsTAT	Pathogenic
188935	NM_000383.4(AIRE):c.1249dup (p.Leu417fs)	Pathogenic
189060	NM_000383.4(AIRE):c.232T>C (p.Trp78Arg)	Pathogenic
1948746	NM_000383.4(AIRE):c.546_547dup (p.Thr183fs)	Pathogenic
1967884	NM_000383.4(AIRE):c.107del (p.Asp36fs)	Pathogenic

SpliceAI

2777 predictions. Top by Δscore:

Variant	Effect	Δscore
21:44286134:TTCAG:T	donor_loss	1.0000
21:44286135:TCAG:T	donor_loss	1.0000
21:44286136:CAGG:C	donor_loss	1.0000
21:44286137:AGGTG:A	donor_loss	1.0000
21:44286138:GG:G	donor_loss	1.0000
21:44286139:GTGG:G	donor_loss	1.0000
21:44286140:T:G	donor_loss	1.0000
21:44289782:G:GT	donor_gain	1.0000
21:44292274:T:G	acceptor_gain	1.0000
21:44293787:A:AG	acceptor_gain	1.0000
21:44293788:G:GG	acceptor_gain	1.0000
21:44293909:GG:G	donor_gain	1.0000
21:44293910:GG:G	donor_gain	1.0000
21:44296371:ACTGG:A	acceptor_gain	1.0000
21:44296373:T:TA	acceptor_gain	1.0000
21:44286727:CAAAG:C	donor_loss	0.9900
21:44286728:AAAG:A	donor_loss	0.9900
21:44286729:AAGG:A	donor_loss	0.9900
21:44286731:GGT:G	donor_loss	0.9900
21:44286732:GT:G	donor_loss	0.9900
21:44286733:T:A	donor_loss	0.9900
21:44289340:A:G	acceptor_gain	0.9900
21:44289803:G:GG	donor_gain	0.9900
21:44291089:T:TA	acceptor_gain	0.9900
21:44292273:A:AG	acceptor_gain	0.9900
21:44292273:AT:A	acceptor_gain	0.9900
21:44292280:T:TA	acceptor_gain	0.9900
21:44292284:T:A	acceptor_gain	0.9900
21:44293783:CCACA:C	acceptor_loss	0.9900
21:44293784:CACA:C	acceptor_loss	0.9900

AlphaMissense

3488 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:44291110:T:A	C299S	0.998
21:44291110:T:C	C299R	0.998
21:44291111:G:C	C299S	0.998
21:44291119:T:A	C302S	0.997
21:44291119:T:C	C302R	0.997
21:44291120:G:C	C302S	0.997
21:44291146:T:C	C311R	0.997
21:44291147:G:A	C311Y	0.997
21:44291155:T:C	C314R	0.997
21:44291167:T:C	F318L	0.997
21:44291169:C:A	F318L	0.997
21:44291169:C:G	F318L	0.997
21:44291170:C:G	H319D	0.997
21:44291172:C:A	H319Q	0.997
21:44291172:C:G	H319Q	0.997
21:44291112:T:G	C299W	0.996
21:44291146:T:A	C311S	0.996
21:44291147:G:C	C311S	0.996
21:44291179:T:C	C322R	0.996
21:44291138:T:C	L308P	0.995
21:44291148:T:G	C311W	0.995
21:44292311:G:C	W335C	0.995
21:44292311:G:T	W335C	0.995
21:44286119:T:A	V38D	0.994
21:44286656:T:A	W78R	0.994
21:44286656:T:C	W78R	0.994
21:44291120:G:A	C302Y	0.994
21:44291121:T:G	C302W	0.994
21:44291138:T:A	L308H	0.994
21:44291147:G:T	C311F	0.993

dbSNP variants (sampled 300 via entrez): RS1000007126 (21:44294441 C>A,T), RS1000081008 (21:44298947 T>A), RS1000169737 (21:44288754 G>C), RS1000283883 (21:44293360 T>TCCAG), RS1000339769 (21:44285547 G>A,C,T), RS1000549864 (21:44297278 G>A), RS1000630685 (21:44297084 G>A,C), RS1000877910 (21:44293713 C>G,T), RS1001249116 (21:44286960 C>T), RS1001307492 (21:44289565 G>A,C), RS1001352930 (21:44290869 C>A,T), RS1001424178 (21:44294871 T>G), RS1001485832 (21:44297596 T>A,C), RS1001862666 (21:44298187 T>C), RS1002404888 (21:44295938 A>G)

Disease associations

OMIM: gene MIM:607358 | disease phenotypes: MIM:240300, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
autoimmune polyendocrine syndrome type 1	Definitive	Autosomal recessive
familial isolated hypoparathyroidism due to impaired PTH secretion	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autoimmune polyendocrine syndrome type 1	Definitive	AR

Mondo (5): autoimmune polyendocrine syndrome type 1 (MONDO:0009411), retinal disorder (MONDO:0005283), autoimmune polyendocrinopathy (MONDO:0017278), autism (MONDO:0005260), familial isolated hypoparathyroidism due to impaired PTH secretion (MONDO:0016000)

Orphanet (2): Autoimmune polyendocrinopathy type 1 (Orphanet:3453), Autoimmune polyendocrinopathy (Orphanet:282196)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000026	Male hypogonadism
HP:0000121	Nephrocalcinosis
HP:0000123	Nephritis
HP:0000134	Female hypogonadism
HP:0000135	Hypogonadism
HP:0000403	Recurrent otitis media
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000580	Pigmentary retinopathy
HP:0000613	Photophobia
HP:0000648	Optic atrophy
HP:0000821	Hypothyroidism
HP:0000829	Hypoparathyroidism
HP:0000846	Adrenal insufficiency
HP:0000872	Hashimoto thyroiditis
HP:0000953	Hyperpigmentation of the skin
HP:0000968	Ectodermal dysplasia
HP:0001045	Vitiligo
HP:0001053	Hypopigmented skin patches
HP:0001081	Cholelithiasis
HP:0001094	Iridocyclitis
HP:0001096	Keratoconjunctivitis
HP:0001133	Constriction of peripheral visual field
HP:0001250	Seizure
HP:0001596	Alopecia
HP:0001733	Pancreatitis
HP:0001746	Asplenia
HP:0001803	Nail pits

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001042_3	Rheumatoid arthritis	4.000000e-09
GCST006959_104	Rheumatoid arthritis	8.000000e-08
GCST009267_16	Dental caries (decayed, missing and filled teeth)	4.000000e-06
GCST90011871_9	Addison’s disease	9.000000e-25
GCST90014023_8	Type 1 diabetes	2.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D012164	Retinal Diseases	C11.768

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases methylation	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
butyraldehyde	increases methylation	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
caprylic aldehyde	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentanal	increases methylation	1
heptanal	increases methylation	1
chloropicrin	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, affects expression	1
Benzo(a)pyrene	affects methylation	1
Cacodylic Acid	affects expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Lead	affects methylation	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methapyrilene	decreases methylation	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Asbestos, Crocidolite	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT01104337	PHASE4	COMPLETED	Drug Interaction Between Paracetamol and Warfarin
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT02295475	PHASE4	COMPLETED	Apixaban for Secondary Prevention of Thromboembolism Among Patients With AntiphosPholipid Syndrome
NCT02303171	PHASE4	UNKNOWN	Use of Warfarin After the First Trimester in Pregnant Women With APS
NCT02326051	PHASE4	COMPLETED	Timing of Initiation of LMWH Administration in Pregnant Women With APS
NCT04624269	PHASE4	UNKNOWN	A Study of Hydroxychloroquine Sulfate in the Treatment of Recurrent Spontaneous Abortion With Antiphospholipid Syndrome
NCT05995600	PHASE4	RECRUITING	Comparison of Clopidogrel-based Antiplatelet Therapy Versus Warfarin As Secondary Prevention Strategy for AntiPhospholipid Syndrome-related STROKE
NCT07087912	PHASE4	RECRUITING	Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01784523	PHASE3	TERMINATED	Hydroxychloroquine for the First Thrombosis Prevention in Antiphospholipid Antibody Positive Patients
NCT02157272	PHASE3	TERMINATED	Rivaroxaban in Thrombotic Antiphospholipid Syndrome