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

Fuller, Jessica LU ; Bogdani, Marika; Tupling, Terry D; Jensen, Richard A; Pefley, Ranae; Manavi, Sahar; Cort, Laura; Blankenhorn, Elizabeth P; Mordes, John P and Lernmark, Åke LU , et al. (2009) In Physiological Genomics 38. p.89-97
Abstract
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... (More)
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. (Less)
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Physiological Genomics
volume
38
pages
89 - 97
publisher
American Physiological Society
external identifiers
  • wos:000267845600010
  • pmid:19351909
  • scopus:67649506344
ISSN
1094-8341
DOI
10.1152/physiolgenomics.00015.2009
language
English
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yes
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a4a52bc5-aead-46cb-8b84-f6d9ba55f228 (old id 1392338)
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http://www.ncbi.nlm.nih.gov/pubmed/19351909?dopt=Abstract
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2009-05-06 09:01:13
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@article{a4a52bc5-aead-46cb-8b84-f6d9ba55f228,
  abstract     = {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&lt;0.001 compared to DR.(lyp/lyp)). Retaining &lt;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&lt;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.},
  author       = {Fuller, Jessica and Bogdani, Marika and Tupling, Terry D and Jensen, Richard A and Pefley, Ranae and Manavi, Sahar and Cort, Laura and Blankenhorn, Elizabeth P and Mordes, John P and Lernmark, Åke and Kwitek, Anne E},
  issn         = {1094-8341},
  language     = {eng},
  pages        = {89--97},
  publisher    = {American Physiological Society},
  series       = {Physiological Genomics},
  title        = {Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene.},
  url          = {http://dx.doi.org/10.1152/physiolgenomics.00015.2009},
  volume       = {38},
  year         = {2009},
}