Two novel truncating variants of the AAAS gene causative of the triple A syndrome

Purpose The triple A syndrome (AAAS) is an inherited condition associated with mutations in the AAAS gene, which encodes a protein of 546 amino acids known as ALADIN (alacrima achalasia adrenal insufficiency neurologic disorder) whose function is not well understood. This protein belongs to the WD-repeat family of regulatory proteins and is located in the nuclear pore complexes. Only a few cohorts of AAAS patients have been reported and fully characterized. Thus, the objective of the present study was to report on a mini cohort of Italian AAAS patients and to get insights on their predisposing genetic defects. Methods Genetic analysis of AAAS gene in triple A syndrome patient and molecular and functional characterization of the novel identified allelic variants. Results Here we describe three newly diagnosed cases of AAAS, in whom genetic analysis allowed us to identify two novel allelic variants in the AAAS gene: the frameshift substitution c.765 dupT (p.Gly256Trp fsX67) in exon 8 and the splice site mutation in intron 11(c.997–2 A > G, IVS11-2A > G). Both variants result in a truncated non-functional protein, as we demonstrate by transcript analysis and expression studies. Conclusions Our findings establish a pathogenic role for both new variants. Moreover, our data highlight the essential role of the C-terminal domain of the protein for its correct targeting and function and underline the importance of sequencing splice sites surrounding the intron–exon junctions to ensure accurate molecular diagnosis and correct genetic counseling in AAAS patients.