Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene

1 Department of Clinical Sciences, Lund University, and Clinical Research Center, Malmö, Sweden 2 Department of Medicine, University of Washington 3 Pacific Northwest Research Institute, Seattle, Washington 4 Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Disea...

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Published in:Physiological genomics 2009-06, Vol.38 (1), p.89-97
Main Authors: Fuller, J. M, Bogdani, M, Tupling, T. D, Jensen, R. A, Pefley, R, Manavi, S, Cort, L, Blankenhorn, E. P, Mordes, J. P, Lernmark, A, Kwitek, A. E
Format: Article
Language:English
Subjects:
Animals
Clinical Medicine
Diabetes Mellitus, Experimental - genetics
Endocrinology and Diabetes
Endokrinologi och diabetes
GTP-Binding Proteins - genetics
Klinisk medicin
Lymphopenia - genetics
Medical and Health Sciences
Medicin och hälsovetenskap
Rats
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Summary:1 Department of Clinical Sciences, Lund University, and Clinical Research Center, Malmö, Sweden 2 Department of Medicine, University of Washington 3 Pacific Northwest Research Institute, Seattle, Washington 4 Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania 5 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 6 Department of Internal Medicine, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa Congenic DRF. f/f rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF. f/f rat line, DRF. f/f rats were crossed to inbred BBDR or DR. lyp/lyp rats to generate congenic sublines that were genotyped and monitored for T1D, and positional candidate genes were sequenced. All (100%) DR. lyp/lyp rats developed T1D by 83 days of age. Reduction of the DRF. f/f F344 DNA fragment by 26 Mb (42.52–68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41–70.17 Mb) ( region 1 ) resulted in 47% protection and significantly delayed onset ( P < 0.001 compared with DR. lyp/lyp ). Retaining
ISSN:1094-8341
1531-2267
DOI:10.1152/physiolgenomics.00015.2009