Three Loci on Mouse Chromosome 6 Influence Onset and Final Incidence of Type I Diabetes in NOD.C3H Congenic Strains

Rogner, Ute Christine; Boîtard, Christian; Morin, Jean Paul; Melanitou, Evie; Avner, Philip

doi:10.1006/geno.2001.6508

Cited by 66 publications

(57 citation statements)

References 58 publications

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“…8,25 Mapping studies in the NOD mouse model have shown that a diabetes susceptibility locus (idd 6) is present on chromosome 6 near the Ly49 gene cluster. 26 In agreement with this finding, NOD mice congenic for C57BL/6 (B6) NK1.1, a marker near the Ly49 cluster, manifested reduced disease incidence and improved NK and NKT cell performance as compared to wild-type NOD mice. 11 To better understand the role activating Ly49 receptors and NK cells may play in the development of diabetes, we analyzed the Ly49 gene cluster of the NOD/ShiLtJ (NOD) inbred mouse.…”

Section: Introductionsupporting

confidence: 63%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

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Section: Introductionsupporting

confidence: 63%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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“…Although 7.8 Mb was the best resolution that we achieved in our study, one could achieve a higher fine-mapping resolution using this strategy by developing more overlapping subcongenics within the locus of interest. Another advantage of using subcongenic lines is that it allows one to test the presence of gene-gene interactions between genes located in separate subregions represented in the panel (Legare and Frankel 2000;Rogner et al 2001). For example, in our data, Ath37 and Ath38 reduced the lesion size by 43 and 41%, respectively.…”

Section: Construction Of Con6 Subcongenic Linesmentioning

confidence: 77%

“…This, coupled with the growing evidence that some of the QTL for complex traits consist of multiple closely linked causal genes (Legare and Frankel 2000;Rogner et al 2001;Liu et al 2002;Diament and Warden 2004;Yalcin et al 2004;Flint et al 2005), lead us to hypothesize that the chromosome 6 locus may also represent such a multigenic region. To examine this, we created a panel of overlapping and reciprocal subcongenic lines from CON6.Ldlr À/À mice and characterized each line for development of atheroma in the proximal aorta.…”

mentioning

confidence: 99%

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

Ghazalpour¹,

Wang²,

Lusis

et al. 2006

Genetics

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We previously mapped a locus on chromosome 6 with a large effect (LOD . 6) on aortic lesion size in a (C57BL/6J 3 CAST/Ei) F 2 cross and identified arachidonate 5-lipoxygenase (5LO) as a candidate gene in this region. Subsequent studies with the 5LO knockout model showed effects on atherosclerosis and aortic aneurysms. We now report detailed genetic analysis of the chromosome 6 locus. We created a panel of overlapping and reciprocal subcongenic lines from the B6.CAST Ldlr À/À chromosome 6 congenic strain (CON6.Ldlr À/À ) and analyzed aortic lesion size in different subcongenic lines. Our results revealed that there are at least two subregions, designated as Ath37 and Ath38 that affect the size of aortic lesions independently of 5LO. We also showed that homozygote 5LO null mice develop smaller atherosclerotic lesions. We conclude that the relation between the mouse chromosome 6 locus and atherosclerosis is complex and is due to at least two genes with large effects within this region. This complexity should be considered when interpreting results of knockout studies.

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“…Indeed, Brodnicki et al (32) have nicely illustrated this by crossing the B6 idd14 locus onto the NOD background and thereby provoking a significantly more robust disease. Interestingly, the idd6 and idd19 regions that condition diabetes susceptibility encompass the NKC (33).…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity

Poirot

Benoist

Mathis

2004

Proc. Natl. Acad. Sci. U.S.A.

151

137

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In both human patients and murine models, the progression from insulitis to diabetes is neither immediate nor inevitable, as illustrated by the innocuous versus destructive infiltrates of BDC2.5 transgenic mice on the nonobese diabetic (NOD) versus C57BL͞6.H-2 g7 genetic backgrounds. Natural killer (NK)-cell-specific transcripts and the proportion of NK cells were increased in leukocytes from the aggressive BDC2.5͞B6.H-2 g7 lesions. NK cell participation was also enhanced in the aggressive lesions provoked by CTLA-4 blockade in BDC2.5͞NOD mice. In this context, depletion of NK cells significantly inhibited diabetes development. NOD and B6.H-2 g7 mice exhibit extensive variation in NK receptor expression, reminiscent of analogous human molecules. NK cells can be important players in type 1 diabetes, a role that was previously underappreciated.type 1 diabetes ͉ mouse model ͉ microarray

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Three Loci on Mouse Chromosome 6 Influence Onset and Final Incidence of Type I Diabetes in NOD.C3H Congenic Strains

Cited by 66 publications

References 58 publications

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity

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