Wolcott-Rallison Syndrome

Clinical, Genetic, and Functional Study of EIF2AK3 Mutations and Suggestion of Genetic Heterogeneity

  1. Valérie Senée1,
  2. Krishna M. Vattem2,
  3. Marc Delépine3,
  4. Lynn A. Rainbow4,
  5. Céline Haton5,
  6. Annick Lecoq6,
  7. Nick J. Shaw7,
  8. Jean-Jacques Robert8,
  9. Raoul Rooman9,
  10. Catherine Diatloff-Zito5,
  11. Jacques L. Michaud10,
  12. Bassan Bin-Abbas11,
  13. Doris Taha12,
  14. Bernard Zabel13,
  15. Piergiorgio Franceschini14,
  16. A. Kemal Topaloglu15,
  17. G. Mark Lathrop3,
  18. Timothy G. Barrett16,
  19. Marc Nicolino6,
  20. Ronald C. Wek2 and
  21. Cécile Julier1
  1. 1Génétique des Maladies Infectieuses et Autoimmunes, INSERM E102, Institut Pasteur, Paris, France
  2. 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
  3. 3Centre National de Génotypage, Evry, France
  4. 4Medical and Molecular Genetics, The Medical School, University of Birmingham, Birmingham, U.K
  5. 5INSERM U383, G. Hospitalier Necker-Enfants Malades, Paris, France
  6. 6Endocrinologie et Diabétologie Infantiles, Hôpital Debrousse, Lyon, France
  7. 7Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, U.K
  8. 8G Hospitalier Necker-Enfants Malades, Paris, France
  9. 9Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium
  10. 10Service de Génétique Médicale, Hôpital Sainte-Justine, Montréal, Canada
  11. 11Department of Pediatrics, King Faisal Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
  12. 12Division of Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
  13. 13Children’s Hospital, University of Mainz, Mainz, Germany
  14. 14Dipartimento di Scienze Pediatriche e dell’Adolescenza, Servizio di Genetica Clinica, Torino, Italy
  15. 15Pediatric Endocrinology, Cukurova University, Adana, Turkey
  16. 16Institute of Child Health, University of Birmingham, Birmingham, U.K
  1. Address correspondence and reprint requests to Cécile Julier, Génétique des Maladies Infectieuses et Autoimmunes, 28, rue du Docteur Roux, 75724 Paris cedex 15, France. E-mail: cjulier{at}pasteur.fr

Abstract

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2α (eIF2α) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

Footnotes

  • V.S. and K.M.V. contributed equally to this work.

    C.H. is currently affiliated with the Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France.

    • Accepted March 22, 2004.
    • Received January 30, 2004.
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