Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

Gabriele       Pogliaghi; Biagio       Cangiano; Paolo       Duminuco; Valeria       Vezzoli; Marco       Bonomi
doi:10.2174/0929866527666200613215449
Abstract

Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.
Keywords: Triple-A Syndrome, AAAS gene, aladin, adrenal insufficiency, achalasia, alacrimia, 4A syndrome, 5A syndrome.
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Graphical Abstract

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DOI https://dx.doi.org/10.2174/0929866527666200613215449	Print ISSN 0929-8665
Publisher Name Bentham Science Publisher	Online ISSN 1875-5305
Protein & Peptide Letters

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

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