AIRE

autoimmune regulator, the group of PHD finger proteins

Basic information

Region (hg38): 21:44285838-44298648

Previous symbols: [ "APECED" ]

Links

ENSG00000160224 ∙ NCBI:326 ∙ OMIM:607358 ∙ HGNC:360 ∙ Uniprot:O43918 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoimmune polyendocrine syndrome type 1 (Definitive), mode of inheritance: AR
• autoimmune polyendocrine syndrome type 1 (Strong), mode of inheritance: AR
• autoimmune polyendocrine syndrome type 1 (Strong), mode of inheritance: AD
• autoimmune polyendocrine syndrome type 1 (Strong), mode of inheritance: AR
• autoimmune polyendocrine syndrome type 1 (Supportive), mode of inheritance: AR
• familial isolated hypoparathyroidism due to impaired PTH secretion (Supportive), mode of inheritance: AD
• autoimmune polyendocrine syndrome type 1 (Moderate), mode of inheritance: AD
• autoimmune polyendocrine syndrome type 1 (Definitive), mode of inheritance: AR
• autoimmune polyendocrine syndrome type 1 (Strong), mode of inheritance: AR
• autoimmune polyendocrine syndrome type 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia	AD/AR	Allergy/Immunology/Infectious; Endocrine	Individuals need life-long follow-up, as sequelae may appear later in life; Endocrine findings can include adrenocortical failure and severe hypocalcemia; Infectious complications, such as candiasis, and septicemia, are frequent, and prompt and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Ophthalmologic	7024719; 3496374; 2348835; 1453436; 9398840; 9398839; 9543115; 9837820; 9717837; 11018166; 11600535; 14557425; 16965330; 17539912; 19758376; 19807739; 25926518

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AIRE gene.

• Polyglandular autoimmune syndrome, type 1 (89 variants)
• not provided (16 variants)
• AIRE-related disorder (3 variants)
• Autoimmune polyglandular syndrome type 1, with reversible metaphyseal dysplasia (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AIRE gene is commonly pathogenic or not. These statistics are base on transcript: . Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	311	9	323
missense	6	23	288	14	4	335
nonsense	26	16	1			43
start loss	5	1	1			7
frameshift	44	38	1			83
splice donor/acceptor (+/-2bp)	6	25	1			32
Total	87	103	295	325	13

Highest pathogenic variant AF is 0.000564949

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AIRE	protein_coding	protein_coding	ENST00000291582	14	12811

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.05e-12	0.313	125194	1	408	125603	0.00163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.00206	351	351	1.00	0.0000226	3420
Missense in Polyphen		89	118.55	0.75071		1221
Synonymous	-0.131	162	160	1.01	0.0000116	1184
Loss of Function	1.09	21	27.1	0.775	0.00000147	289

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00147	0.00144
Ashkenazi Jewish	0.00	0.00
East Asian	0.00153	0.00152
Finnish	0.00522	0.00514
European (Non-Finnish)	0.00193	0.00189
Middle Eastern	0.00153	0.00152
South Asian	0.000229	0.000229
Other	0.00199	0.00196

dbNSFP

Source: dbNSFP

• Function: 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) (PubMed:26084028). 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 (By similarity). 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 (PubMed:26084028). 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 (By similarity). {ECO:0000250|UniProtKB:Q9Z0E3, ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:18292755, ECO:0000269|PubMed:26084028, ECO:0000305|PubMed:19302042, ECO:0000305|PubMed:26972725}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:10677297, ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:11275943, ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11600535, ECO:0000269|PubMed:11836330, ECO:0000269|PubMed:12050215, ECO:0000269|PubMed:12173302, ECO:0000269|PubMed:12625412, ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:15712268, ECO:0000269|PubMed:16114041, ECO:0000269|PubMed:18292755, ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947, ECO:0000269|PubMed:9398839, ECO:0000269|PubMed:9888391}. Note=The disease is caused by mutations 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 (PubMed:14974083). Heterozygous mutations within the PHD1 domain have dominant-negatif effects and cause organ-specific autoimmune diseases (PubMed:26084028). 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 (PubMed:27426947). {ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947}.
• Pathway: Primary immunodeficiency - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.593

Intolerance Scores

• loftool: 0.124
• rvis_EVS: -0.57
• rvis_percentile_EVS: 19.01

Haploinsufficiency Scores

• pHI: 0.196
• hipred: N
• hipred_score: 0.438
• ghis: 0.434

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.923

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Aire
• Phenotype: vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; neoplasm; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; growth/size/body region phenotype; hematopoietic system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: peripheral T cell tolerance induction;central tolerance induction to self antigen;regulation of transcription, DNA-templated;regulation of translation;immune response;humoral immune response;chemokine production;negative thymic T cell selection;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;thymus epithelium morphogenesis;regulation of thymocyte migration
• Cellular component: nucleus;cytoplasm;nuclear body
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;protein binding;zinc ion binding;histone binding;identical protein binding;transcription regulatory region DNA binding;translation regulator activity