title: Mutant WD-repeat protein in triple-A syndrome.
abstract: Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. 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. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. 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. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Tullio-Pelet
authors.forename: R
authors.initials: R
authors.lastname: Salomon
authors.forename: S
authors.initials: S
authors.lastname: Hadj-Rabia
authors.forename: C
authors.initials: C
authors.lastname: Mugnier
authors.forename: M H
authors.initials: MH
authors.lastname: de Laet
authors.forename: B
authors.initials: B
authors.lastname: Chaouachi
authors.forename: F
authors.initials: F
authors.lastname: Bakiri
authors.forename: P
authors.initials: P
authors.lastname: Brottier
authors.forename: L
authors.initials: L
authors.lastname: Cattolico
authors.forename: C
authors.initials: C
authors.lastname: Penet
authors.forename: M
authors.initials: M
authors.lastname: Bégeot
authors.forename: D
authors.initials: D
authors.lastname: Naville
authors.forename: M
authors.initials: M
authors.lastname: Nicolino
authors.forename: J L
authors.initials: JL
authors.lastname: Chaussain
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000309:Adrenal Insufficiency / Q000235:genetics*; D000352:Africa, Northern; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D003062:Codon / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004931:Esophageal Achalasia / Q000235:genetics*; D019143:Evolution, Molecular; D020224:Expressed Sequence Tags; D005796:Genes; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009422:Nervous System Diseases / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins; D010375:Pedigree; D017354:Point Mutation; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013577:Syndrome; D014985:Xerophthalmia / Q000235:genetics*
chemical_list: C416506:AAAS protein, human; D003062:Codon; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D011506:Proteins