Loss of Kinase Activity in a Patient With Wolcott-Rallison Syndrome Caused By a Novel Mutation in the EIF2AK3 Gene
- From the University Children’s Hospital, Division of Pediatric Endocrinology/Diabetology, Zurich, Switzerland
Wolcott-Rallison syndrome (WRS) is an autosomal recessive disorder characterized by neonatal or early infancy type 1 diabetes, epiphyseal dysplasia, and growth retardation. Mutations in the EIF2AK3 gene, encoding the eukaryotic initiation factor 2α-kinase 3 (EIF2AK3), have been found in WRS patients. Here we describe a girl who came to our attention at 2 months of age with severe hypertonic dehydration and diabetic ketoacidosis. A diagnosis of type 1 diabetes was made and insulin treatment initiated. Growth retardation and microcephaly were also present. Anti-islet cell autoantibodies were negative, and mitochondrial diabetes was excluded. Imaging revealed a hypoplastic pancreas and typical signs of spondylo-epiphyseal dysplasia. The diagnosis of WRS was therefore made at age 5 years. Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense serine 877 proline mutation. The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2α (eIF2α). This is the first case in which the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level. Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans, and we suggest EIF2AK3 as a possible target for therapeutic intervention in diabetes.
Address correspondence and reprint requests to Anna Biason-Lauber, MD, University Children’s Hospital, Division of Endocrinology/Diabetology, Steinwiesstrasse 75, 8032 Zurich, Switzerland. E-mail:.
Received for publication 15 December 2001 and accepted in revised form 15 April 2002.
A.B.-L. and M.L.-M. contributed equally to this work.
eIF2, eukaryotic initiation factor 2; EIF2AK3, eukaryotic initiation factor 2α-kinase 3; ER, endoplasmic reticulum; IA2, insulinoma antibody 2; IAA, insulin autoantibody; WRS, Wolcott-Rallison syndrome.