Re: EIF2AK3 Mutations in Patients with Wolcott-Rallison Syndrome

Abstract

To the Editor: I read with interest the report of a new case of Wolcott-Rallison syndrome by Marafie et al1 and would like to further highlight the molecular basis of this syndrome. Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by early-onset permanent diabetes mellitus, multiple epiphyseal dysplasia, growth retardation, and variable other systemic manifestations. Delepine et al2 mapped WRS to chromosome 2p12, and identified in two consanguineous families with WRS two mutations in EIF2AK3, the gene encoding the eukaryotic translation initiation factor 2-alpha kinase.3 The mutations segregated with the disorder of each of the families. These results provided evidence for the role of EIF2AK# deficiency in WRS at the molecular level. They describe a homozygous missense serine 877 proline mutation of EIF2AK3 gene in a 5-year-old girl with WRS, and found that the mutated kinase was unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha). A comprehensive clinical, genetic, and functional study of EIF2AK3 mutations in WRS was recently published.4 Twelve families with WRS, totaling 18 cases were studied. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. The patient with no EIF2AK3 involvement did not have any of the variable clinical manifestations associated with WRS, suggesting both genetic and clinical heterogeneity between this variant form of WRS5,6 were included in this study;4 two different EIF2AK3 mutations were identified in these families [560GA and del (184bp) in exon 15/intron 15]. Another novel EIF2AK3 mutation was recently described in a child with WRS.7 In summary, EIF2AK3 mutations have been identified in at least 18 WRS cases from 12 families. This demonstrates that EIF2AK3 gene plays a major role in the pathophysiology of WRS. In addition, EIF2aK3 kinase activity appears to be essential for pancreatic islet cell function and bone development in humans.