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

Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder cha racterized by permanent neonatal or early infancy insulin-dependent diabete s. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a lat er age. Other frequent multisystemic manifestations include hepatic and ren al dysfunction, mental retardation and cardiovascular abnormalities(1-5). O n the basis of two consanguineous families, we mapped WRS to a region of le ss than 3 cM on chromosome 2p12, with maximal evidence of linkage and homoz ygosity at 4 microsatellite markers within an interval of approximately 1 c M. The gene encoding the eukaryotic translation initiation factor 2-alpha k inase 3 (EIF2AK3) resides in this interval; thus we explored it as a candid ate. We identified distinct mutations of EIF2AK3 that segregated with the d isorder in each of the families, The first mutation produces a truncated pr otein 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 evide nce for the role of EIF2AK3 in WRS, The identification of this gene may pro vide insight into the understanding of the more common forms of diabetes an d other pathologic manifestations of WRS.