1. Wolcott-Rallison Syndrome
- Author
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Bassan Bin-Abbas, Annick Lecoq, Jean Jacques Robert, Jacques L. Michaud, Nick Shaw, R. Rooman, Céline Haton, Doris Taha, G. Mark Lathrop, Krishna M. Vattem, Ronald C. Wek, Marc Delepine, Bernard Zabel, A. Kemal Topaloglu, Piergiorgio Franceschini, Catherine Diatloff-Zito, Valérie Senée, Timothy Barrett, Cécile Julier, Marc Nicolino, and Lynn A. Rainbow
- Subjects
Genetics ,Mutation ,Genetic heterogeneity ,Endocrinology, Diabetes and Metabolism ,Dwarfism ,Biology ,medicine.disease ,medicine.disease_cause ,Multiple epiphyseal dysplasia ,Internal Medicine ,medicine ,Missense mutation ,EIF2AK3 ,Kinase activity ,Wolcott–Rallison syndrome - 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 (
- Published
- 2004
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