A novel homozygous mutation of the AIRE gene in an APECED patient from Pakistan: case report and review of the literature

Autoimmune-poly-endocrinopathy-candidiasis–ectodermal-dystrophy syndrome (APECED)is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator(AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the followingdisorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism(CHP), and Addison’s disease. APECED develops at high incidence in Finns, Sardinians,and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes.In this manuscript, we report the clinical, endocrinological, and molecular features of a16-year-old female patient from Pakistan living in Italy and presenting the major APECEDclinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarianfailure, chronic bronchopneumopathy, vitiligo, Hashimoto’s thyroiditis emerged asassociated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C(p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis.This is the first reported mutation within the nuclear localization signal (NLS) thatis associated with APECED. The NLS mutation affects the nuclear import of classicaltranscription factors through nuclear pore by recognition of nuclear import receptors,the importin α molecules. By displaying crystal structures of the peptide containing theKRK basic residue cluster bound to α importins, we show that p.R132S replacement in131-KRK-133 does not reproduce these interactions. Thus, we propose that the novelmutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein.The present case report is added to a limited series of Pakistani APECED patients whowe reviewed from the scientific literature, mostly diagnosed on clinical findings.