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Wolcott-Rallison Syndrome

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

¹ Génétique des Maladies Infectieuses et Autoimmunes, INSERM E102, Institut Pasteur, Paris, France
² Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
³ Centre National de Génotypage, Evry, France
⁴ Medical and Molecular Genetics, The Medical School, University of Birmingham, Birmingham, U.K
⁵ INSERM U383, G. Hospitalier Necker-Enfants Malades, Paris, France
⁶ Endocrinologie et Diabétologie Infantiles, Hôpital Debrousse, Lyon, France
⁷ Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, U.K
⁸ G Hospitalier Necker-Enfants Malades, Paris, France
⁹ Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium
¹⁰ Service de Génétique Médicale, Hôpital Sainte-Justine, Montréal, Canada
¹¹ Department of Pediatrics, King Faisal Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
¹² Division of Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
¹³ Children’s Hospital, University of Mainz, Mainz, Germany
¹⁴ Dipartimento di Scienze Pediatriche e dell’Adolescenza, Servizio di Genetica Clinica, Torino, Italy
¹⁵ Pediatric Endocrinology, Cukurova University, Adana, Turkey
¹⁶ Institute of Child Health, University of Birmingham, Birmingham, U.K

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 2 (eIF2) 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.

Abbreviations: eIF2, eukaryotic initiation factor 2; GST, glutathione S-transferase; WRS, Wolcott-Rallison syndrome

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