Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene.
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 <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 with 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 <20% of islets in nondiabetic 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.
Fuller
J M
JM
Department of Clinical Sciences, Lund University, Clinical Research Center, Malmö, Sweden. jfuller@u.washington.edu
Bogdani
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Tupling
T D
TD
Jensen
R A
RA
Pefley
R
R
Manavi
S
S
Cort
L
L
Blankenhorn
E P
EP
Mordes
J P
JP
Lernmark
A
A
Kwitek
A E
AE
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D008231:Lymphopenia / Q000235:genetics*; D051381:Rats
D019204:GTP-Binding Proteins; C494977:Gimap5 protein, rat