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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 orcid , 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
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
LU publication?
yes
id
a4a52bc5-aead-46cb-8b84-f6d9ba55f228 (old id 1392338)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19351909?dopt=Abstract
date added to LUP
2016-04-04 08:36:30
date last changed
2022-01-29 03:42:57
@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}},
  doi          = {{10.1152/physiolgenomics.00015.2009}},
  volume       = {{38}},
  year         = {{2009}},
}