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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Wolcott, C.D. & Rallison, M.V. Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J. Pediatr. 80, 292–297 (1972).
Goumy, P. et al. Syndrome de transmission recessive autosomique, associant un diabete congenital et des desoirdres de la croissances des epiphyses. Arch. Fr. Pediatr. 37, 323–328 (1980).
Stoss, H., Pesch, H.-J., Pontz, B., Otten, A. & Spranger, J. Wolcott-Rallison syndrome: diabetes mellitus and spondylo-epiphyseal dysplasia. Eur. J. Pediatr. 138, 120–129 (1982).
Al-Gazali, L.I., Makia, S. & Hall, C.M. Wolcott-Rallison syndrome. Clin. Dysmorphol. 4, 227–233 (1995).
Thornton, C.M., Carson, D.J. & Stewart, F.J. Autopsy findings in the Wolcott-Rallison syndrome. Pediatr. Pathol. Lab. Med. 17, 487–496 (1997).
Inoue, H. et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genet. 20, 143–148 (1998).
Winter, W.E., Nakamura, M. & House, D.V. Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol. Metab. Clin. North. Am. 28, 765–785 (1999).
Froguel, P. & Velho, G. Molecular genetics of maturity-onset diabetes of the young. Trends Endocrinol. Metab. 10, 142–146 (1999).
Barroso, I. et al. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880–883 (1999).
Nicolino, P.M., Dupin, H., Macabeo, V., Treppoz, S. & Chatelain, P.G. Wolcott-Rallison syndrome (diabetes mellitus and spondyloepiphyseal dysplasia): a plausible existence of a gene(s) important for the maturation of neonatal pancreatic β cell function. Horm. Res. 50, A215 (1998).
Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. & Gruss, P. The Pax4 gene is essential for differentiation of insulin-producing β-cells in the mammalian pancreas. Nature 386, 399–402 (1997).
Bonthron, D.T., Dunlop, N., Barr, D.G., El Sanousi, A.A. & Al Gazali, L.I. Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome. J. Med. Genet. 35, 288–292 (1998).
Stewart, F.J. et al. Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q 11–12. Clin. Genet. 49, 152–155 (1996).
Shi, Y. et al. Characterization of a mutant pancreatic eIF-2α kinase, PEK, and co-localization with somatostatin in islet δ cells. J. Biol. Chem. 274, 5723–5730 (1999).
Hayes, S.E., Conner, L.J., Stramm, L.E. & Shi, Y. Assignment of pancreatic eIF2α kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization. Cytogenet. Cell Genet. 86, 327–328 (1999).
Hanks, S.K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).
Shi, Y. et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 α-subunit kinase, PEK, involved in translational control. Mol. Cell. Biol. 18, 7499–7509 (1998).
Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999).
Srivastava, S.P., Kumar, K.U. & Kaufman, R.J. Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J. Biol. Chem. 273, 2416–2423 (1998).
Goodison, S., Kenna, S. & Ashcroft, S.J. Control of insulin gene expression by glucose. Biochem. J. 285, 563–568 (1992).
Gilligan, M. et al. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J. Biol. Chem. 271, 2121–2125 (1996).
Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371, 161–164 (1994).
Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).
Mein, C.A. et al. A search for type I diabetes susceptibility genes in families from the United Kingdom. Nature Genet. 19, 297–300 (1998).
Concannon, P. et al. A second generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19, 292–296 (1998).
Hanis, C.L. et al. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13, 161–166 (1996).
Pratley, R.E. et al. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J. Clin. Invest. 101, 1757–1764 (1998).
Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl Acad. Sci. USA 81, 3443–3446 (1984).
Rosenblum, B.B. et al. New dye-labeled terminators for improved DNA sequencing patterns. Nucleic Acids Res. 25, 4500–4504 (1997).
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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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). https://doi.org/10.1038/78085
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