AIRE – Autoimmune polyendocrine syndrome type 1

Autoimmune regulator (AIRE) is the causal gene for autoimmune polyendocrine syndrome type 1 (APS1), an autosomal recessive disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. APS1 has a prevalence of ~1:80 000 in Northern Europe and presents in childhood with variable ectodermal dystrophy and multi-organ autoimmunity (PMID:9398839).

Genetic analyses across >300 probands from over 34 unrelated families worldwide have identified more than 60 distinct loss-of-function AIRE variants—including nonsense (e.g. c.769C>T (p.Arg257Ter)), frameshift, splice-site, and missense mutations affecting PHD and SAND domains—supporting strong AR genetic evidence (PMID:9921903). Founder alleles such as c.769C>T (p.Arg257Ter) in Finnish and Sardinian cohorts account for ~70% of mutant chromosomes, while private variants (e.g. c.653-1G>A) illustrate locus heterogeneity.

Segregation of biallelic AIRE variants with APS1 features has been documented in at least 16 consanguineous and non-consanguineous kindreds, with compound heterozygous or homozygous LoF alleles co-segregating in siblings and unaffected carriers remaining asymptomatic (PMID:11207636). A representative variant is c.415C>T (p.Arg139Ter), which truncates the SAND domain and abolishes function (PMID:9398839).

Functional assays demonstrate that wild-type AIRE localizes to nuclear speckles in medullary thymic epithelial cells (mTECs) and activates transcription of peripheral tissue antigens. Nonsense and missense mutations disrupt subnuclear targeting and transactivation capacity in reporter assays (PMID:10677297) and systematic domain deletions confirm essential roles for the HSR, SAND, and PHD motifs in AIRE function (PMID:12471056).

Mechanistically, biallelic AIRE deficiency impairs central tolerance by reducing expression of tissue-restricted antigens in the thymus, allowing autoreactive T cells to escape deletion and drive multi-organ autoimmunity. Dominant-negative variants (e.g. p.Gly228Trp) further illustrate dosage-sensitive regulation of AIRE activity (PMID:16114041).

Integration of genetic and experimental data over >25 years establishes a Definitive gene-disease association for AIRE in APS1, with Strong genetic evidence from LoF variant segregation and Strong functional evidence from in vitro and in vivo models. Key variants such as c.415C>T (p.Arg139Ter) provide diagnostic landmarks.

Key Take-home: Biallelic AIRE loss-of-function mutations cause APS1 via defective central tolerance, warranting early genetic testing for rapid diagnosis and management.

References

• Nature Genetics | 1997 | Positional cloning of the APECED gene. PMID:9398839
• Human Genetics | 1998 | Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). PMID:9921903
• Clinical Endocrinology | 2001 | Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. PMID:11207636
• American Journal of Human Genetics | 2000 | Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. PMID:10677297
• Human Molecular Genetics | 2002 | Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. PMID:12471056
• Human Mutation | 2005 | Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. PMID:16114041

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