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Åke Lernmark

Principal investigator

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Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene.

Author

  • Jessica Fuller
  • Marika Bogdani
  • Terry D Tupling
  • Richard A Jensen
  • Ranae Pefley
  • Sahar Manavi
  • Laura Cort
  • Elizabeth P Blankenhorn
  • John P Mordes
  • Åke Lernmark
  • Anne E Kwitek

Summary, in English

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, monitored for T1D and positional candidate genes 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 Mb-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 to DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (Region 2) resulted in 28% protection and also delayed onset (p<0.001 compared to DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 Region 1 interval to approximately 670 Kb and Region 2 to the 340 Kb proximal to Gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels but less than 20% of islets in non-diabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12 and 13 as candidate genes in Region 1 and Znf467 and Atp6v0e2 as candidate genes in Region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4. Key words: Type 1 diabetes, BB rat, T cell receptor, autoimmune.

Department/s

  • Diabetes and Celiac Unit

Publishing year

2009

Language

English

Pages

89-97

Publication/Series

Physiological Genomics

Volume

38

Document type

Journal article

Publisher

American Physiological Society

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes and Celiac Unit

ISBN/ISSN/Other

  • ISSN: 1094-8341