Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.
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.
Senée
Valérie
V
Génétique des Maladies Infectieuses et Autoimmunes, INSERM E102, Institut Pasteur, Paris, France.
Vattem
Krishna M
KM
Delépine
Marc
M
Rainbow
Lynn A
LA
Haton
Céline
C
Lecoq
Annick
A
Shaw
Nick J
NJ
Robert
Jean-Jacques
JJ
Rooman
Raoul
R
Diatloff-Zito
Catherine
C
Michaud
Jacques L
JL
Bin-Abbas
Bassan
B
Taha
Doris
D
Zabel
Bernard
B
Franceschini
Piergiorgio
P
Topaloglu
A Kemal
AK
Lathrop
G Mark
GM
Barrett
Timothy G
TG
Nicolino
Marc
M
Wek
Ronald C
RC
Julier
Cécile
C
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*
C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase