Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene

The triple autosomal recessive disorder characterized oy adrenal insufficie ncy, achalasia and alacrima, The frequent association with a variety of neu rological features may result in a severely disabling disease, We previousl y mapped the syndrome to a 6 cM interval on chromosome 12q13 and have now r efined the critical region to 0 cM between KRT8 and D12S1651, Overlapping b acterial artificial chromosome (BAC) sequences of a high resolution BAC/P1- derived artificial chromosome (PAC) contig were screened for gene content a nd a novel gene encoding a 546 amino acid polypeptide was identified. In ni ne triple A syndrome patients eight different homozygous and compound heter ozygous mutations were found in this gene, most of them leading to a trunca ted 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 th e disease. The predicted protein belongs to the family of WD repeat-contain ing proteins which exhibit a high degree of functional diversity including regulation of signal transduction, RNA processing and transcription.