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Normal Function
The AAAS gene provides instructions for making a protein called ALADIN. ALADIN belongs to a family of proteins called nucleoporins that help transport molecules between the nucleus and the fluid surrounding the nucleus (cytoplasm).
ALADIN is abundant in the adrenal glands, the brain, and the digestive system. Within cells, ALADIN is found in the nuclear envelope, the structure that surrounds the nucleus and separates it from the rest of the cell. ALADIN acts as a gatekeeper that controls which molecules can enter or exit the nucleus, helping to ensure that the proteins that cells need to function reach the proper locations within the nucleus at the appropriate times.
ALADIN is also believed to help protect cells in the adrenal glands from the damage caused by unstable oxygen-containing molecules.
Health Conditions Related to Genetic Changes
Triple A syndrome
Several variants (also called mutations) in the AAAS gene have been found to cause triple A syndrome, also called Allgrove syndrome. This condition is characterized by difficulty moving food through the esophagus (achalasia), insufficient hormone production by the adrenal glands (adrenal insufficiency), and an absence or a reduction of the secretion of tears (alacrima).
The variants in the AAAS gene that are associated with triple A syndrome cause cells to produce a version of ALADIN that does not function properly. This impairs the communication and movement of molecules between the nucleus and the rest of the cell. Researchers suspect that these changes may prevent the proteins that are essential for DNA repair from entering the nucleus. When DNA damage is not repaired, the cell can become unstable and die. It is unclear exactly how variants in the AAAS gene lead to the specific signs and symptoms seen in people with triple A syndrome.
More About This Health ConditionOther Names for This Gene
- AAA
- AAASb
- achalasia, adrenocortical insufficiency, alacrimia
- achalasia, adrenocortical insufficiency, alacrimia (Allgrove, triple-A)
- ADRACALA
- ADRACALIN
- ALADIN
- GL003
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, Bei T, Bjornson B, Russell L, Chanoine JP, Tsagarakis S, Kalsner L, Stratakis C. Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005. Clin Genet. 2005 Sep;68(3):215-21. doi: 10.1111/j.1399-0004.2005.00482.x. Citation on PubMed
- Cehic M, Mitrovic K, Vukovic R, Milenkovic T, Kovacevic G, Todorovic S, Panic Zaric S, Cvetkovic D, Paripovic A, Huebner A, Koehler K, Quitter F. Very early and severe presentation of Triple A syndrome - case report and review of the literature. Front Endocrinol (Lausanne). 2024 Sep 24;15:1431383. doi: 10.3389/fendo.2024.1431383. eCollection 2024. Citation on PubMed
- Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5823-7. doi: 10.1073/pnas.1031047100. Epub 2003 May 2. Citation on PubMed
- Dumic M, Barisic N, Kusec V, Stingl K, Skegro M, Stanimirovic A, Koehler K, Huebner A. Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. Eur J Pediatr. 2012 Oct;171(10):1453-9. doi: 10.1007/s00431-012-1745-1. Epub 2012 Apr 28. Citation on PubMed
- Flokas ME, Tomani M, Agdere L, Brown B. Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach. Pediatric Health Med Ther. 2019 Aug 29;10:99-106. doi: 10.2147/PHMT.S173081. eCollection 2019. Citation on PubMed
- Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001 Feb 1;10(3):283-90. doi: 10.1093/hmg/10.3.283. Citation on PubMed
- Kind B, Koehler K, Lorenz M, Huebner A. The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope. Biochem Biophys Res Commun. 2009 Dec 11;390(2):205-10. doi: 10.1016/j.bbrc.2009.09.080. Epub 2009 Sep 24. Citation on PubMed
- Kiriyama T, Hirano M, Asai H, Ikeda M, Furiya Y, Ueno S. Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. Biochem Biophys Res Commun. 2008 Oct 3;374(4):631-4. doi: 10.1016/j.bbrc.2008.07.088. Epub 2008 Jul 26. Citation on PubMed
- Krumbholz M, Koehler K, Huebner A. Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation. Biochem Cell Biol. 2006 Apr;84(2):243-9. doi: 10.1139/o05-198. Citation on PubMed
- Sheikh MM, Bittar K. Allgrove Syndrome. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK560701/ Citation on PubMed
- Storr HL, Kind B, Parfitt DA, Chapple JP, Lorenz M, Koehler K, Huebner A, Clark AJ. Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism. Mol Endocrinol. 2009 Dec;23(12):2086-94. doi: 10.1210/me.2009-0056. Epub 2009 Oct 23. Citation on PubMed
- Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de Laet MH, Chaouachi B, Bakiri F, Brottier P, Cattolico L, Penet C, Begeot M, Naville D, Nicolino M, Chaussain JL, Weissenbach J, Munnich A, Lyonnet S. Mutant WD-repeat protein in triple-A syndrome. Nat Genet. 2000 Nov;26(3):332-5. doi: 10.1038/81642. Citation on PubMed
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