Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats

  1. Jessica M. Fuller1,
  2. Anne E. Kwitek2,
  3. Tyson J. Hawkins1,
  4. Daniel H. Moralejo3,
  5. Wen Lu1,
  6. Terry D. Tupling1,
  7. Armand J. MacMurray1,
  8. Gretta Borchardt2,
  9. Michael Hasinoff2 and
  10. Åke Lernmark1
  1. 1Department of Medicine, University of Washington, Seattle, Washington
  2. 2Department of Physiology, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin
  3. 3Department of Comparative Medicine, University of Washington, Seattle, Washington
  1. Address correspondence and reprint requests to Jessica Fuller, University of Washington, Department of Medicine, 1959 NE Pacific St., Box 357710, Seattle, WA 98195. E-mail: jfuller{at}u.washington.edu

Abstract

Failure to express the Gimap5 protein is associated with lymphopenia (lyp) and linked to spontaneous diabetes in the diabetes-prone BioBreeding (BBDP) rat. Gimap5 is a member of seven related genes located within 150 Kb on rat chromosome 4. Congenic DR.lyp/lyp rats, where BBDP lyp was introgressed onto the diabetes-resistant BBDR background (BBDR.BBDP.lyp/lyp), all develop diabetes between 46 and 81 days of age (mean ± SE, 61 ± 1), whereas DR.lyp/+ and DR.+/+ rats are nonlymphopenic and diabetes resistant. In an intercross between F1(BBDP x F344) rats, we identified a rat with a recombination event on chromosome 4, allowing us to fix 33 Mb of F344 between D4Rat253 and D4Rhw6 in the congenic DR.lyp rat line. Gimap1 and Gimap5 were the only members of the Gimap family remaining homozygous for the BBDP allele. Offspring homozygous for the F344 allele (f/f) between D4Rat253 and D4Rhw6 were lymphopenic (85 of 85, 100%) but did not develop diabetes (0 of 85). During rescue of the recombination, 102 of 163 (63%) rats heterozygous (b/f) for the recombination developed diabetes between 52 and 222 days of age (88 ± 3). Our data demonstrate that introgression of a 33-Mb region of the F344 genome, proximal to the mutated Gimap5 gene, renders the rat diabetes resistant despite being lymphopenic. Spontaneous diabetes in the BB rat may therefore be controlled, in part, by a diabetogenic factor(s), perhaps unrelated to the Gimap5 mutation on rat chromosome 4.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted August 31, 2006.
    • Received May 24, 2006.
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