Re: EIF2AK3 Mutations in Patients with Wolcott-Rallison Syndrome

Abstract

LettersRe: EIF2AK3 Mutations in Patients with Wolcott-Rallison Syndrome Doris TahaMD Doris Taha Search for more papers by this author Published Online:4 Aug 2005https://doi.org/10.5144/0256-4947.2005.350aSectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionTo 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.7In 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.ARTICLE REFERENCES:1. Marafie MJ, Redha MA, Al-Naggar RL. "Wolcott-Rallison syndrome in a Bedouin boy" . Ann Saudi Med. 2004; 24(6):476-9. Google Scholar2. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome" . Nat Genet. 2000; 24(4):406-9. Google Scholar3. Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ. "Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene" . Diabetes. 2002; 51(7):2301-5. Google Scholar4. Senee V, Vattem KM, Delepine M, et al. "Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2ªK3 mutations and suggestion of genetic heterogeneity" . Diabetes. 2044; 53(7):1876-83. Google Scholar5. Bin-Abbas B, Shahib S, Hainau B, Al-Ashwal A. "Wolcott-Rallison syndrome: Clinical, radiological, and histological findings in a Saudi Child" . Ann Saudi Med. 2001; 21:73-74. Google Scholar6. Bin-Abbas B, Al-Mulhim A, Al-Ashwal A. "Wolcott-Rallison syndrome in two siblings with isolated central hypothyroidism" . Am J Med Genet. 2002; 111(2):187-90. Google Scholar7. Iyer S, Korada M, Rainbow L, Kirk J, Brown RM, Shaw N, Barett TG. "Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature" . Acta Paediatr. 2004; 93(9):1195-201. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 25, Issue 4July-August 2005 Metrics History Published online4 August 2005 InformationCopyright © 2005, Annals of Saudi MedicineThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.PDF download