Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is an autosomal recessive disorder resulting from mutations in the autoimmune regulator (AIRE) gene, typically causing severe, childhood-onset organ-specific autoimmunity.
• Dominant-negative AIRE mutations in specific domains can lead to milder, incompletely penetrant phenotypes with later onset, often mimicking organ-specific autoimmune diseases.

Purpose of the Study:

• To investigate novel phenotypes associated with heterozygous AIRE mutations.
• To functionally assess the dominant-negative effects of AIRE variants in vitro.
• To highlight the diagnostic challenges and management strategies for families with AIRE-related disorders.

Main Methods:

• Genetic analysis of patients with unexplained immunodeficiency or autoimmunity.
• In vitro functional assays to evaluate the dominant-negative effects of identified heterozygous AIRE mutations.
• Clinical phenotyping and autoantibody analysis in affected families.

Main Results:

• Identification of additional families presenting with a spectrum of phenotypes, including immunodeficiency, enteropathy, vitiligo, and asymptomatic carrier status.
• Demonstration of dominant-negative effects for heterozygous AIRE variants.
• Observation that APS-1-specific autoantibodies can suggest pathogenic AIRE variants, but their absence does not exclude them.

Conclusions:

• Heterozygous AIRE mutations can cause a broader range of clinical presentations than previously recognized.
• Functional studies are crucial for assessing the pathogenicity of AIRE variants.
• Close clinical follow-up of individuals and families with identified AIRE variants is recommended.