Mutant WD-repeat protein in triple-A syndrome

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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 alacrima1,2,3. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system4,5,6, 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 well7,8. 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.

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Figure 1: Barium swallow of the oesophagus in a triple-A patient with achalasia.
Figure 2: Mutant triple-A chromosome haplotypes in North African patients, physical map of the triple-A interval at 12q13, and genomic organization of AAAS.
Figure 3: Mutations of AAAS and abnormal transcripts.
Figure 4: ALADIN amino acid sequence and AAAS mRNA expression.

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Acknowledgements

We thank O. Poch, J.M. Van der Winden, A. Rotschild, J. Zlotogora, J.C. Carel, P.F. Bougnères, C. Goizet, D. Lacombe, C. Weill, P. Adiceam, R. Brauner, P. Chatelain, Y. Le Bouc, D. Rieu, M. Dumic, M. Pombo, R. Sandrini and L. de Lacerda for discussions, referring patients and support; and G. Gyapay, T. Attié-Bitach, J.M. Rozet, H. El Shanti, O. Gribouval, M. Dailhat, X. Ferrera and Y. Deris for discussions and help in preparing this manuscript. This work was supported by grants from the AFM and the Assistance Publique-Hôpitaux de Paris (AOA95).

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Correspondence to Stanislas Lyonnet.

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Tullio-Pelet, A., Salomon, R., Hadj-Rabia, S. et al. Mutant WD-repeat protein in triple-A syndrome. Nat Genet 26, 332–335 (2000) doi:10.1038/81642

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