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: A Tullio-Pelet, R Salomon, S Hadj-Rabia, C Mugnier, M H de Laet, B Chaouachi, F Bakiri, P Brottier, L Cattolico, C Penet, M Bégeot, D Naville, M Nicolino, J L Chaussain, J Weissenbach, A Munnich, S Lyonnet
• Journal: Nature genetics (Nat Genet) Vol. 26 Issue 3 Pg. 332-5 (Nov 2000) ISSN: 1061-4036 [Print] United States
• PMID: 11062474 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AAAS protein, human
• Codon
• Nerve Tissue Proteins
• Nuclear Pore Complex Proteins
• Proteins

Topics

• Abnormalities, Multiple (genetics)
• Adrenal Insufficiency (genetics)
• Africa, Northern
• Amino Acid Motifs
• Amino Acid Sequence
• Chromosomes, Artificial, Bacterial (genetics)
• Chromosomes, Human, Pair 12 (genetics)
• Codon (genetics)
• Consanguinity
• DNA Mutational Analysis
• Esophageal Achalasia (genetics)
• Evolution, Molecular
• Expressed Sequence Tags
• Genes
• Haplotypes
• Humans
• Linkage Disequilibrium
• Molecular Sequence Data
• Nerve Tissue Proteins (chemistry, deficiency, genetics, physiology)
• Nervous System Diseases (genetics)
• Nuclear Pore Complex Proteins
• Pedigree
• Point Mutation
• Proteins (chemistry, genetics, physiology)
• Repetitive Sequences, Amino Acid
• Sequence Alignment
• Sequence Homology, Amino Acid
• Species Specificity
• Syndrome
• Xerophthalmia (genetics)