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

• A glutamic acid deletion (DeltaE) in the AAA+ protein torsinA causes DYT1 dystonia [10].
• Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study) [11].
• Chromatographic evidence that the AAA-coding isoacceptor of lysine tRNA primes DNA synthesis in murine mammary tumor virus [12].
• Aromatic AA (AAA) and methionine were elevated in cirrhosis (p < 0.001 each), increasing with disease stage, and normalized after OLT [13].
• The branched-chain amino acids (BCAA: valine, leucine, isoleucine) were decreased in the group of patients with liver diseases compared with the control group, whereas the aromatic amino acids (AAA: phenylalanine, tyrosine) were increased [14].

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

• It is caused by mutations in a gene that is normally referred to as the triple A syndrome gene (AAAS) and which has recently been shown to encode a nuclear pore protein named ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder) [19].
• On the other hand hepatocytes, enteric smooth muscle and fibroblasts had relatively little or no detectable AAAS mRNA [19].
• Consistent with a role for AAAS in adrenal function, we detected high levels of its mRNA in the adrenal cortex [19].
• In both the peripheral and central nervous systems, AAAS mRNA was abundantly expressed [19].
• Although neuronal expression of AAAS mRNA was striking, non-neuronal cells including those of the circumventricular organs and fibrous astrocytes also expressed AAAS mRNA [19].

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].

References