Mutant WD-repeat protein in triple-A syndrome (original) (raw)

Nature Genetics volume 26, pages 332–335 (2000)Cite this article

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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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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Author notes

  1. Rémi Salomon and Smaïl Hadj-Rabia: These authors contributed equally to this work.

Authors and Affiliations

  1. Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393 and Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
    Anna Tullio-Pelet, Rémi Salomon, Smaïl Hadj-Rabia, Claude Mugnier, Clothilde Penet & Arnold Munnich
  2. Service de Chirurgie Pédiatrique, Hôpital d'Enfants, Bruxelles, Belgium
    Marc-Henri de Laet
  3. Service de Chirurgie Pédiatrique B, Hôpital d'Enfants, Tunis, Tunisia
    Beji Chaouachi
  4. Service d'Endocrinologie, Hôpital Bologhine, Alger, Algeria
    Fawzi Bakiri
  5. Genoscope and CNRS FRE 2231, Evry, France
    Philippe Brottier, Laurence Cattolico & Jean Weissenbach
  6. Unité INSERM-INRA U-418, Lyon, France
    Martine Bégeot & Danielle Naville
  7. Service d'Endocrinologie Infantile, Hôpital Debrousse, Lyon, France
    Marc Nicolino
  8. Service d'Endocrinologie Pédiatrique, Hôpital Saint-Vincent de Paul, Paris, France
    Jean-Louis Chaussain
  9. Stanislas Lyonnet

Authors

  1. Anna Tullio-Pelet
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  2. Rémi Salomon
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  3. Smaïl Hadj-Rabia
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  4. Claude Mugnier
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  5. Marc-Henri de Laet
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  6. Beji Chaouachi
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  7. Fawzi Bakiri
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  8. Philippe Brottier
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  9. Laurence Cattolico
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  10. Clothilde Penet
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  11. Martine Bégeot
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  12. Danielle Naville
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  13. Marc Nicolino
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  14. Jean-Louis Chaussain
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  15. Jean Weissenbach
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  16. Arnold Munnich
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  17. Stanislas Lyonnet
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Corresponding author

Correspondence toStanislas 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). https://doi.org/10.1038/81642

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