Triple A (Allgrove) syndrome: a rare entity
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Background

The triple A (Allgrove) syndrome was first described in two pairs of siblings by in 1978. Since then, a number of families have been reported, all of them displaying an autosomal recessive pattern of inheritance....

In 1996, Weber et al. localized the disease gene on chromosome 12q13. The triple A gene, designated AAAS, was cloned in 2000 by Tullio-Pelet et al. and Handschug et al. The AAAS gene consists of 16 exons, encoding for a 546 amino acid protein called ALADIN (Al acrimia-A chalasia-aD renal I nsufficiency N eurologic disorder). The gene expression is ubiquitous, but notably high in the adrenal gland, gastrointestinal tract and brain. ALADIN protein belongs to the WD-repeat family of regulatory proteins, with functions ranging from trans membrane signaling and transcription, to cell division and intracellular trafficking . The precise function of ALADIN is unknown, it is part of the nuclear pore complex. Missense, nonsense and splicing mutations in AAAS gene cause the protein to mislocalize to the cytoplasm. Cells from subjects with Allgrove syndrome do not show morphologic abnormalities in the nuclei, nuclear envelope or nuclear pore complexes, suggesting that mutations in AAAS gene result in functional, rather than structural, abnormalities in the nuclear pore complex. Frameshift, stop codon and functionally significant mutations lead to a more severe phenotype, probably occurring by a loss of function effect on the protein. Mutations of the AAAS gene cannot be identified in all clinically diagnosed AAAS patients. This finding raises the possibility of mutations in regulatory or deeper intronic sequences, or genetic heterogeneity.....

https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-39-39
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