Mutant WD-repeat protein in triple-A syndrome

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autos omal recessive disorder characterized by adrenocorticotropin hormone (ACTH) -resistant adrenal insufficiency, achalasia of the oesophageal cardia and a lacrima(1-3) Whereas several lines of evidence indicate that triple-A syndr ome results from the abnormal development of the autonomic nervous system(4 -6), late-onset progressive neurological symptoms (including cerebellar ata xia, peripheral neuropathy and mild dementia) suggest that the central nerv ous system may be involved in the disease as well(7,8). Using fine-mapping based on linkage disequilibrium in North African inbred families, we identi fied a short ancestral haplotype on chromosome 12q23 (<1 cM), sequenced a B AC contig encompassing the triple-a minimal region and identified a novel g ene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated pa tients and ascribed the founder effect in North African families to a singl e splice-donor site mutation that occurred more than 2,400 years ago. The p redicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficie ncy neurologic disorder), belongs to the WD-repeat family of regulatory pro teins, indicating a new disease mechanism involved in triple-A syndrome. Th e expression of the gene in both neuroendocrine and cerebral structures poi nts to a role in the normal development of the peripheral and central nervo us systems.