Journal article
Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene
Physiological genomics, v 38(1), pp 89-97
2009
PMID: 19351909
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 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.
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Details
- Title
- Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene
- Creators
- Jessica Fuller - Diabetes and Celiac UnitMarika BogdaniTerry D TuplingRichard A JensenRanae PefleySahar ManaviLaura CortElizabeth P BlankenhornJohn P MordesÅke Lernmark - Diabetes and Celiac UnitAnne E Kwitek
- Publication Details
- Physiological genomics, v 38(1), pp 89-97
- Publisher
- American Physiological Society (APS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; [Retired Faculty]
- Web of Science ID
- WOS:000267845600010
- Scopus ID
- 2-s2.0-67649506344
- Other Identifier
- 991014877832704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Genetics & Heredity
- Physiology