title: Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.
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 2alpha (eIF2alpha) 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.
authors.affiliation: Génétique des Maladies Infectieuses et Autoimmunes, INSERM E102, Institut Pasteur, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Senée
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Vattem
authors.forename: Marc
authors.initials: M
authors.lastname: Delépine
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Rainbow
authors.forename: Céline
authors.initials: C
authors.lastname: Haton
authors.forename: Annick
authors.initials: A
authors.lastname: Lecoq
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Shaw
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Robert
authors.forename: Raoul
authors.initials: R
authors.lastname: Rooman
authors.forename: Catherine
authors.initials: C
authors.lastname: Diatloff-Zito
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Bassan
authors.initials: B
authors.lastname: Bin-Abbas
authors.forename: Doris
authors.initials: D
authors.lastname: Taha
authors.forename: Bernard
authors.initials: B
authors.lastname: Zabel
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Franceschini
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Barrett
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: Cécile
authors.initials: C
authors.lastname: Julier
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics*; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D009154:Mutation; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome; D019892:eIF-2 Kinase / Q000235:genetics*
chemical_list: C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase