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A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)

Abstract

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet ß-cells and neurons.

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Figure 1: Pedigrees of WFS families, with individuals designated by disease status (solid symbols affected, open symbols unaffected), and with derived haplotypes of chromosome 4p markers.
Figure 2: Physical map of the WFS critical region.
Figure 3: Expression of WFS1 mRNA in adult tissues.
Figure 4: Hydrophobicity analysis was conducted13 using a window size of 9 aa.
Figure 5: Comparison of human and mouse WFS1 protein sequences.
Figure 6: Co-segregation of WFS1 mutations with the disease phenotype in WFS families.

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Acknowledgements

We are grateful to the patients, their families and physicians for participating in this study. We acknowledge S. Nanko, T. Ikeuchi, K. Yamamoto, Y. Hoshino, H.Yokoyama, S. Hoshino, S. Niwa and N. Nakao for care of patients, compiling clinical data and obtaining patient samples. The authors thank Y. Kora, Y. Mizukami, C. Welling, B. Wilson and C. Iannotti for technical assistance, and J. Wokurka for preparation of the manuscript. We also thank J. Rice for initial help with power calculations for linkage analysis, P. Goodfellow for helpful advice throughout the project and C. Helms for construction of the meiotic map of chromosome 4p. S. Chissoe, R. Wilson and E. Mardis gave guidance with the shotgun sequencing. This work was supported in part by NIH grants DK16746 and DK20579 (M.A.P.), DK07120 (P.B.), HG00100 (H.D.-K.), and DK38494 (M.M.), Grant-in-Aid for Creative Basic Research (10NP0201) from the Ministry of Education, Science, Sports and Culture of Japan (Y.O.), Grants-in-Aid for Scientific Research (10671074) from the Ministry of Education, Science, Sports and Culture of Japan (Y.T.) and a Mentor-Based Fellowship Award from the American Diabetes Association (Y.T., H.I.).

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Correspondence to M. Alan Permutt.

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Inoue, H., Tanizawa, Y., Wasson, J. et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 20, 143–148 (1998). https://doi.org/10.1038/2441

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