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EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome


Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities1,2,3,4,5. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.

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Figure 1: Characterization of extended sets of microsatellite markers in the region linked to WRS on chromosome 2 in families WRS1 and WRS2.
Figure 2: Sequence chromatograms for the regions of the mutations in the index patients and normal controls from the WRS1 family (a; 1103insT) and the WRS2 family (b; 1832G→A).
Figure 3: Effect of EIF2AK3 mutations on the protein.

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We thank V. Macabéo for referring family WRS1; the families for collaboration; and E. Melanitou and E. Villard for helpful comments on the manuscript. C.J. is a Wellcome Trust Senior Fellow.

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Correspondence to Cécile Julier.

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Delépine, M., Nicolino, M., Barrett, T. et al. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25, 406–409 (2000).

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