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Experimental Diabetes Research
Volume 2009 (2009), Article ID 835650, 10 pages
http://dx.doi.org/10.1155/2009/835650
Research Article

Sequence Variation and Expression of the Gimap Gene Family in the BB Rat

1Diabetes and Endocrinology Research Center, University of Washington, 815 Mercer Street, Building A, S130, Seattle, WA 98109, USA
2Department of Biological and Chemical Sciences, Salish Kootenai College, 58138 Hwy 93, Pablo, P.O. Box 70, MT 59855, USA
3Department of Clinical Sciences, Clinical Research Center, Lund University, Entrance 72, Building 91:10, 20502 Malmö, Sweden
4Department of Medicine, University of Washington, 1959 N.E. Pacific Street, Seattle, P.O. Box 357710, WA 98195, USA
5Department of Comparative Medicine, University of Washington, 1959 N.E. Pacific Street, Seattle, P.O. Box 357190, WA 98195, USA
6Department of Internal Medicine, University of Iowa, 375 Newton Road, 3111B MERF, Iowa City, IA 52242, USA

Received 9 December 2008; Accepted 8 February 2009

Academic Editor: Anjan Kowluru

Copyright © 2009 Elizabeth A. Rutledge et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Positional cloning of lymphopenia (lyp) in the BB rat revealed a frameshift mutation in Gimap5, a member of at least seven related GTPase Immune Associated Protein genes located on rat chromosome 4q24. Our aim was to clone and sequence the cDNA of the BB diabetes prone (DP) and diabetes resistant (DR) alleles of all seven Gimap genes in the congenic DR.lyp rat line with 2 Mb of BB DP DNA introgressed onto the DR genetic background. All (100%) rats are lymphopenic and develop type 1 diabetes (T1D) by 84 days of age while rats remain T1D and lyp resistant. Among the seven Gimap genes, the Gimap5 frameshift mutation, a mutant allele that produces no protein, had the greatest impact on lymphopenia in the rat. Gimap4 and Gimap1 each had one amino acid substitution of unlikely significance for lymphopenia. Quantitative RT-PCR analysis showed a reduction in expression of all seven Gimap genes in spleen and mesenteric lymph nodes when compared to . Only four; Gimap1, Gimap4, Gimap5, and Gimap9 were reduced in thymus. Our data substantiates the Gimap5 frameshift mutation as the primary defect with only limited contributions to lymphopenia from the remaining Gimap genes.