AAAS – triple-A syndrome

Triple-A syndrome (Allgrove syndrome) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the AAAS gene, encoding the nuclear pore protein ALADIN (AAAS, triple-A syndrome). Clinically, it is defined by the triad of alacrima, achalasia, and ACTH-resistant adrenal insufficiency, often with progressive neurological involvement (PMID:12730363).

Genetic studies have identified numerous AAAS mutations across diverse populations. In Tunisian patients, a cohort of 26 unrelated individuals uniformly presented with the classical triad and neurological signs; 25 harbored a homozygous splice-donor mutation c.1331+1G>A and one carried a homozygous nonsense mutation c.856C>T (p.Arg286Ter) (PMID:27133709). Founder effects for c.1331+1G>A have been demonstrated in North African kindreds, facilitating targeted molecular diagnostics. Earlier linkage and sequencing studies in Puerto Rican and North American families corroborated autosomal recessive inheritance, with recurrent AAAS mutations including c.43C>A (p.Gln15Lys) and IVS14+1G>A (PMID:11701718, PMID:12429595).

Functional assays in patient fibroblasts and GFP-tagged mutants confirm that disease-associated missense, nonsense, and frameshift variants mislocalize ALADIN from nuclear pore complexes, impairing nucleocytoplasmic transport without gross NPC structural defects (PMID:12730363, PMID:16609705). Knock-down of AAAS in adrenocortical cells further demonstrates reduced CYP17A1/CYP21A2 expression, oxidative stress susceptibility, and disrupted steroidogenesis (PMID:25867024).

No studies have refuted the AAAS–triple-A syndrome association. The consistency of phenotype in over 200 genetically confirmed patients from >50 families, segregation in consanguineous and non-consanguineous pedigrees, and concordant functional data establish a definitive gene–disease relationship. Molecular testing of AAAS is therefore recommended in all patients with alacrima and at least one additional cardinal feature. Early genetic diagnosis informs adrenal crisis prevention, Heller’s myotomy for achalasia, and lifelong endocrine surveillance.

Key take-home: Biallelic AAAS mutations unequivocally underlie triple-A syndrome, justifying targeted genetic testing in unexplained adrenal insufficiency with alacrima or achalasia and enabling timely clinical management.

References

• Archives of Medical Research • 2016 • Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome PMID:27133709
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome PMID:12730363
• Biochemistry and Cell Biology • 2006 • Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome – shedding light on an unexpected splice mutation PMID:16609705
• The Journal of Clinical Endocrinology and Metabolism • 2001 • Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin PMID:11701718
• Brain: A Journal of Neurology • 2002 • Clinical and genetic characterization of families with triple A (Allgrove) syndrome PMID:12429595
• PLoS One • 2015 • Role of ALADIN in human adrenocortical cells for oxidative stress response and steroidogenesis PMID:25867024

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