Delineation of the Molecular Defects in the AIRE Gene in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients from Southern Italy

Abstract

In this study, we have carried out molecular analysis of the AIRE (autoimmune regulator) gene in 11 patients (from 8 families) affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, originating from a restricted area of Southern Italy (the Salento peninsula in Puglia). Of the 16 mutant AIRE alleles from the 8 probands studied, 12 carried a missense mutation (W78R in 9, P539L in 2, and P252L in 1), 2 carried the Q358X nonsense mutation, and 2 carried the 1058delT frameshift mutation. All these mutations except the 1058delT are novel. Each of the detected mutations either predicts a premature termination of the protein or results in a nonconservative amino acid change, most likely adversely affecting the function of the protein. The W78R missense mutation is relatively common in these patients, having been detected (in homozygosity or compound heterozygosity) in 6 of the 8 probands tested, indicating the presence of a founder effect. The results of this study contribute to the delineation of the molecular pathology of the AIRE gene and enhance our ability to perform a molecular diagnosis in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.

Identification of two novel mutations in the first Sicilian APECED patient with no R203X mutation in AIRE gene and review of Italian APECED genotypes

“…The novel variants of sequence, the S107C and Q108fs mutations (c.319A>T, c.322delC), are different from one another, since the first one is a missense mutation, whilst the second one is a small deletion of 1 bp. Both mutations affect the HSR domain of AIRE protein; in agreement with previous studies, it is likely that the AIRE protein loses its homodimerization properties, as already suggested (Meloni et al, 2002). From a phenotypic point of view the present Table 1 AIRE gene PCR and sequencing primers.…”

“…The most common and recurrent mutations worldwide are R257X and 1094-1106del13, which have been detected in 90% of the identified alleles from north-eastern Italian patients (Cervato et al, 2009). By contrast, both these mutations are very rare in the patients from southern Italian regions, such as Sardinia (Rosatelli et al, 1998), Apulia (Meloni et al, 2002), Sicily (De Luca et al, 2008), Campania (Capalbo et al, 2012) and Calabria (Betterle et al, 2011). In each of these regions APECED genotype is characterized by a peculiar mutation, which is different from those detected in the other ones: R139X in Sardinia, W78R in Apulia and R203X in Sicily.…”

“…In Italy three hot spot areas have now been identified: in Sardinia (1:14 400) (Rosatelli et al, 1998), in Apulia (1:35 000) (Meloni et al, 2002) and in a small town of the Venetian region (1:4400) (Betterle et al, 2002) respectively.…”

DAXX Is a New AIRE-interacting Protein

“…The last LXXLL motif and the flanking PXX-PXP sequence are essential for the transactivation capacity of AIRE (18). This finding is supported by the presence in this region of an autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy causing mutation (25). Previous studies have shown that AIRE is present in soluble high molecular weight complexes, and this evidence suggests the existence of several interacting proteins (9).…”

Syndrome Apeced ou polyendocrinopathie auto-immune de type 1

“…Elle est principalement localisée au niveau nucléaire, mais peut être transloquée dans le cytoplasme [12]. Elle présente des caractéristiques structurales typiques d'un facteur de transcription (ses différents domaines fonctionnels sont représentés dans la figure 1 [13] Gène AIRE et protéine AIRE1 populations norvégiennes, nord-américaines, anglaises, irlandaises, et dans le Nord-Ouest de la France, la mutation c.967-979del13 (p.Leu323SerfsX51) est la plus répandue. La mutation c.254A > G (p.Tyr85Cys) est typique des patients juifs iraniens, alors que la mutation c.415C > T (p.Arg139Stop) demeure la plus fréquente en Sardaigne (figure 1).…”