title: Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.
abstract: The triple A syndrome (MIM 231550) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. The frequent association with a variety of neurological features may result in a severely disabling disease. We previously mapped the syndrome to a 6 cM interval on chromosome 12q13 and have now refined the critical region to 0 cM between KRT8 and D12S1651. Overlapping bacterial artificial chromosome (BAC) sequences of a high resolution BAC/P1-derived artificial chromosome (PAC) contig were screened for gene content and a novel gene encoding a 546 amino acid polypeptide was identified. In nine triple A syndrome patients eight different homozygous and compound heterozygous mutations were found in this gene, most of them leading to a truncated protein suggesting loss of function. RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple A syndrome, supporting the hypothesis that mutations in this triple A syndrome gene (AAAS) are responsible for the disease. The predicted protein belongs to the family of WD repeat-containing proteins which exhibit a high degree of functional diversity including regulation of signal transduction, RNA processing and transcription.
authors.affiliation: Children's Hospital, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Handschug
authors.forename: S
authors.initials: S
authors.lastname: Sperling
authors.forename: S J
authors.initials: SJ
authors.lastname: Yoon
authors.forename: S
authors.initials: S
authors.lastname: Hennig
authors.forename: A J
authors.initials: AJ
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Huebner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000309:Adrenal Insufficiency; D000595:Amino Acid Sequence; D001483:Base Sequence; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004931:Esophageal Achalasia; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007765:Lacrimal Apparatus / Q000002:abnormalities*; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D013577:Syndrome
chemical_list: D004247:DNA