Two novel mutations of the AIRE protein affecting its homodimerization properties

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Autoimmune Polyendocrine Syndrome type 1 (APECED) is a rare autoimmune disorder.
• Mutations in the AIRE gene are the primary cause of APECED.
• The HSR domain of the AIRE protein is crucial for its function.

Purpose of the Study:

• To identify and characterize novel mutations in the AIRE gene in Italian patients with APECED.
• To investigate the functional impact of these novel mutations on AIRE protein homodimerization.

Main Methods:

• Genetic sequencing to identify mutations in the AIRE gene.
• Two-hybrid assay in a yeast system to assess protein-protein interactions.

Main Results:

• Two novel compound heterozygous mutations, c.230T>C (p.F77S) and c.64_69del (p.V22_D23del), were identified in the AIRE gene's HSR domain.
• These mutations were found in conjunction with known pathogenic variants (c.994+5G>T and c.232T>A).
• The identified mutations disrupted the homodimerization of the AIRE protein.

Conclusions:

• The novel AIRE mutations identified contribute to APECED pathogenesis by impairing protein homodimerization.
• Defective AIRE protein function due to impaired homodimerization leads to the autoimmune manifestations of APECED.