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Gene Review

AAAS  -  achalasia, adrenocortical insufficiency,...

Homo sapiens

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Disease relevance of AAAS

  • Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction [1].
  • Myoclonus and generalized digestive dysmotility in triple A syndrome with AAAS gene mutation [2].
  • AAAS meeting. The flip side of obesity research [3].
  • Allgrove syndrome with features of familial dysautonomia: A novel mutation in the AAAS gene [4].
  • Bilateral PAAS were present in 18 patients (47.4%); 14 (36.8%) also had an abdominal aortic aneurysm (AAA); associated AAAS were twice as common in patients with bilateral PAAS (9/18, 50%) compared to those with unilateral PAAS (5/20, 25%; p=NS) [5].

Psychiatry related information on AAAS

  • Both the AAA and VOA subdivisions of the anterior cingulate cortex were significantly activated during the interference condition; however, only the signal intensity change within the VOA correlated with task performance [6].

High impact information on AAAS

  • Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals [7].
  • The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome [7].
  • AAA proteins are molecular chaperones that facilitate a variety of functions, including membrane fusion, proteolysis, peroxisome biogenesis, endosome sorting and meiotic spindle formation, but functions for the SF7 AAA proteins are largely unknown [8].
  • Fidgetin is the first mutant AAA protein found in a mammalian developmental mutant, thus defining a new role for these proteins in embryonic development [8].
  • Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia [9].

Chemical compound and disease context of AAAS


Biological context of AAAS

  • Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS [1].
  • Here we report cloning and characterization of a novel splice variant of human AAAS, which we named AAAS-v2, which is located on the human chromosome 12p13 [15].
  • DNA sequencing of PCR-amplified fragments from the 16 exons of the AAAS gene revealed compound heterozygosity for a new, out-of-frame 5-bp deletion in exon 15, c1368-1372delGCTCA, and a previously-described nonsense mutation in exon 9, c938C>T, R286X [16].
  • The lack of AAAS mutations in eight patients and negative linkage to chromosome 12q13 in three families are suggestive of genetic heterogeneity [17].
  • AAAS conference explores ethical aspects of large pedigree genetic research [18].

Anatomical context of AAAS


Associations of AAAS with chemical compounds

  • It has been inferred from DNA sequence analyses that in echinoderm mitochondria not only the usual asparagine codons AAU and AAC, but also the usual lysine codon AAA, are translated as asparagine by a single mitochondrial (mt) tRNAAsn with the anticodon GUU [20].
  • These findings imply that Psi35 of echinoderm mt tRNAAsn actually serves to decode the unusual asparagine codon AAA, resulting in the alteration of the genetic code in echinoderm mitochondria [20].
  • The three aromatic amino acids are examined, AAA = phenylalanine, tyrosine, or tryptophan [21].
  • Expression of the cleavage-resistant mutant Rad9 DDD/AAA appears to protect the cell from DNA damage-induced apoptosis [22].
  • Our results suggest that the organization of the Esigma(54) regulatory centre, and in particular the conformation adopted by the sigma(54) Region I and the DNA fork junction structure during open complex formation, is communicated to the AAA activator via the conserved T residue of the GAFTGA motif [23].

Other interactions of AAAS

  • Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene [24].
  • Lebrón, Managing Editor, CCT, AAAS, 1333 H Street, NW, Washington, DC 20005 USA, FAX 202-842-2868 [25].
  • Mutation analysis revealed a homozygous point mutation in exon 4 of his AAAS gene, changing codon 119 encoding Arg (CGA) to a stop codon (TGA) (R119X) [26].
  • Familial occurrence of adrenocortical insufficiency in two brothers with Allgrove syndrome. A case report of 4A (Allgrove) syndrome with epilepsy and a new AAAS gene mutation [27].
  • Clearly, other genes that cause FGD remain to be discovered, and further work is required on the functions of MRAP and ALADIN in the expectation that they will provide insights into essential biological processes and perhaps identify key therapeutic strategies and targets for these diseases [28].

Analytical, diagnostic and therapeutic context of AAAS

  • Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS [15].
  • In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene [29].
  • The 16 exons of the AAAS gene (or ALADIN) were screened for mutations using the denaturing high-performance liquid chromatography method [30].
  • To determine the individual contribution of the two AAA domains to ATP hydrolysis and GFP unfolding we performed extensive site-directed mutagenesis of the Walker A, Walker B, sensor-1, and pore residues in both AAA domains [31].
  • Examination by electron microscopy of BchI solutions in the presence of ATP demonstrated that BchI, like other AAA proteins, forms oligomeric ring structures [32].


  1. Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005. Brooks, B.P., Kleta, R., Stuart, C., Tuchman, M., Jeong, A., Stergiopoulos, S.G., Bei, T., Bjornson, B., Russell, L., Chanoine, J.P., Tsagarakis, S., Kalsner, L., Stratakis, C. Clin. Genet. (2005) [Pubmed]
  2. Myoclonus and generalized digestive dysmotility in triple A syndrome with AAAS gene mutation. Roubergue, A., Apartis, E., Vidailhet, M., Mignot, C., Tullio-Pelet, A., Lyonnet, S., de Villemeur, T.B. Mov. Disord. (2004) [Pubmed]
  3. AAAS meeting. The flip side of obesity research. Enserink, M. Science (2001) [Pubmed]
  4. Allgrove syndrome with features of familial dysautonomia: A novel mutation in the AAAS gene. Ismail, E.A., Tulliot-Pelet, A., Mohsen, A.M., Al-Saleh, Q. Acta Paediatr. (2006) [Pubmed]
  5. Popliteal artery aneurysms. Factors associated with thromboembolism and graft failure. Martelli, E., Ippoliti, A., Ventoruzzo, G., De Vivo, G., Ascoli Marchetti, A., Pistolese, G.R. International angiology : a journal of the International Union of Angiology. (2004) [Pubmed]
  6. Stroop performance in normal control subjects: an fMRI study. Gruber, S.A., Rogowska, J., Holcomb, P., Soraci, S., Yurgelun-Todd, D. Neuroimage (2002) [Pubmed]
  7. Mutant WD-repeat protein in triple-A syndrome. Tullio-Pelet, A., Salomon, R., Hadj-Rabia, S., Mugnier, C., de Laet, M.H., Chaouachi, B., Bakiri, F., Brottier, P., Cattolico, L., Penet, C., Bégeot, M., Naville, D., Nicolino, M., Chaussain, J.L., Weissenbach, J., Munnich, A., Lyonnet, S. Nat. Genet. (2000) [Pubmed]
  8. The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development. Cox, G.A., Mahaffey, C.L., Nystuen, A., Letts, V.A., Frankel, W.N. Nat. Genet. (2000) [Pubmed]
  9. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Hazan, J., Fonknechten, N., Mavel, D., Paternotte, C., Samson, D., Artiguenave, F., Davoine, C.S., Cruaud, C., Dürr, A., Wincker, P., Brottier, P., Cattolico, L., Barbe, V., Burgunder, J.M., Prud'homme, J.F., Brice, A., Fontaine, B., Heilig, B., Weissenbach, J. Nat. Genet. (1999) [Pubmed]
  10. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. Goodchild, R.E., Dauer, W.T. J. Cell Biol. (2005) [Pubmed]
  11. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Ziegler, D., Hanefeld, M., Ruhnau, K.J., Meissner, H.P., Lobisch, M., Schütte, K., Gries, F.A. Diabetologia (1995) [Pubmed]
  12. Chromatographic evidence that the AAA-coding isoacceptor of lysine tRNA primes DNA synthesis in murine mammary tumor virus. Waters, L.C. Virology (1981) [Pubmed]
  13. Plasma amino acids in cirrhosis and after liver transplantation: influence of liver function, hepatic hemodynamics and circulating hormones. Tietge, U.J., Bahr, M.J., Manns, M.P., Böker, K.H. Clinical transplantation. (2002) [Pubmed]
  14. Brain amino acid abnormalities in liver disease--a postmortem study. Musshoff, F., Schmidt, P., Madea, B., Schoenemeier, S., Buerrig, K.F., Jacob, B., Bonte, W., Daldrup, T. J. Forensic Sci. (2003) [Pubmed]
  15. Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS. Li, X., Ji, C., Gu, J., Xu, J., Jin, Z., Sun, L., Zou, X., Lin, Y., Sun, R., Wang, P., Gu, S., Mao, Y. Mol. Biol. Rep. (2005) [Pubmed]
  16. Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report. Brooks, B.P., Kleta, R., Caruso, R.C., Stuart, C., Ludlow, J., Stratakis, C.A. BMC ophthalmology [electronic resource]. (2004) [Pubmed]
  17. The triple A syndrome is due to mutations in ALADIN, a novel member of the nuclear pore complex. Huebner, A., Kaindl, A.M., Knobeloch, K.P., Petzold, H., Mann, P., Koehler, K. Endocr. Res. (2004) [Pubmed]
  18. AAAS conference explores ethical aspects of large pedigree genetic research. Glass, R.M. JAMA (1992) [Pubmed]
  19. Identification of the sites of expression of triple A syndrome mRNA in the rat using in situ hybridisation. Storr, H.L., Clark, A.J., Priestley, J.V., Michael, G.J. Neuroscience (2005) [Pubmed]
  20. The presence of pseudouridine in the anticodon alters the genetic code: a possible mechanism for assignment of the AAA lysine codon as asparagine in echinoderm mitochondria. Tomita, K., Ueda, T., Watanabe, K. Nucleic Acids Res. (1999) [Pubmed]
  21. Cation-pi interactions: structures and energetics of complexation of Na+ and K+ with the aromatic amino acids, phenylalanine, tyrosine, and tryptophan. Ruan, C., Rodgers, M.T. J. Am. Chem. Soc. (2004) [Pubmed]
  22. Caspase-3-mediated cleavage of Rad9 during apoptosis. Lee, M.W., Hirai, I., Wang, H.G. Oncogene (2003) [Pubmed]
  23. Communication between Esigma(54) , promoter DNA and the conserved threonine residue in the GAFTGA motif of the PspF sigma-dependent activator during transcription activation. Bordes, P., Wigneshweraraj, S.R., Chaney, M., Dago, A.E., Morett, E., Buck, M. Mol. Microbiol. (2004) [Pubmed]
  24. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Handschug, K., Sperling, S., Yoon, S.J., Hennig, S., Clark, A.J., Huebner, A. Hum. Mol. Genet. (2001) [Pubmed]
  25. Is the medical world ready for electronic journals? Huth, E.J. The Online journal of current clinical trials [electronic resource]. (1992) [Pubmed]
  26. Two cases of Allgrove syndrome with mutations in the AAAS gene. Kinjo, S., Takemoto, M., Miyako, K., Kohno, H., Tanaka, T., Katsumata, N. Endocr. J. (2004) [Pubmed]
  27. Familial occurrence of adrenocortical insufficiency in two brothers with Allgrove syndrome. A case report of 4A (Allgrove) syndrome with epilepsy and a new AAAS gene mutation. Kurca, E., Grofik, M., Kucera, P., Varsik, P. Neuro Endocrinol. Lett. (2005) [Pubmed]
  28. Genetics of ACTH insensitivity syndromes. Clark, J.L., Metherell, L.A., Naville, D., Begeot, M., Huebner, A. Ann. Endocrinol. (Paris) (2005) [Pubmed]
  29. Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin. Sandrini, F., Farmakidis, C., Kirschner, L.S., Wu, S.M., Tullio-Pelet, A., Lyonnet, S., Metzger, D.L., Bourdony, C.J., Tiosano, D., Chan, W.Y., Stratakis, C.A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  30. Idiopathic achalasia is not allelic to alacrima achalasia adrenal insufficiency syndrome at the ALADIN locus. Di Nardo, G., Tullio-Pelet, A., Annese, V., Stanghellini, V., Barbara, G., Latiano, A., Andriulli, A., Cremon, C., Salvioli, B., Volta, U., Corinaldesi, R., Lyonnet, S., De Giorgio, R. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. (2005) [Pubmed]
  31. VAT, the thermoplasma homolog of mammalian p97/VCP, is an N domain-regulated protein unfoldase. Gerega, A., Rockel, B., Peters, J., Tamura, T., Baumeister, W., Zwickl, P. J. Biol. Chem. (2005) [Pubmed]
  32. Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase. Fodje, M.N., Hansson, A., Hansson, M., Olsen, J.G., Gough, S., Willows, R.D., Al-Karadaghi, S. J. Mol. Biol. (2001) [Pubmed]
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