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GENDER-SPECIFIC GENETIC DISSECTION OF DIABETES IN A RODENT MODEL IDENTIFIES ICA1 AND NDUFA4 AS MAJOR CANDIDATE GENES.

Authors: Barkalifa, R  Yagil, Y  Yagil, C 
Citation: Barkalifa R, etal., Physiol Genomics. 2010 Jun 8.
Pubmed: (View Article at PubMed) PMID:20530722
DOI: Full-text: DOI:10.1152/physiolgenomics.00042.2010

Objective: The aim of the study was to initiate a sex-specific investigation of the molecular basis of diabetes, using a genomic approach in the Cohen Diabetic rat model of diet-induced type 2 diabetes. Research Design and Methods: We used an F2 population resulting from a cross between Cohen Diabetic sensitive (CDs) and resistant (CDr) and consisting of 132 males and 159 females to detect relevant QTLs by linkage and co-segregation analyses. To confirm the functional relevance of the QTL, we applied the "chromosome substitution" strategy. We identified candidate genes within the QTL and studied their differential expression. We sequenced the differentially expressed candidate genes to account for differences in their expression. Results: We confirmed in this new cross in males a previously detected major QTL on rat chromosome 4 (RNO4); we identified in females this major QTL as well. We found 3 additional diabetes-related QTLs on RNO11, 13 and 20 in females only. We pursued the investigation of the QTL on RNO4 and generated a CDs.4(CDr) consomic strain which provided us with functional confirmation for the contribution of the QTL to the diabetic phenotype in both sexes. We successfully narrowed the QTL span to 2.6 cM and identified within it 6 candidate genes, but only two of which, Ica1 (Islet cell autoantigen 1) and Ndufa4 (NADH dehydrogenase ubiquinone) were differentially expressed between CDs and CDr. We sequenced the exons and promoter regions of Ica1 and Ndufa4 but did not identify sequence variations between the strains. Conclusions: The detection of the QTL on RNO4 in both sexes suggests involvement of Ica1, Ndufa4, the Golgi apparatus, the mitochondria and genetic susceptibility to dietary-environmental factors in the pathophysiology of diabetes in our model. The additional sex-specific QTLs are likely to account for differences in the diabetic phenotype between the sexes.

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RGD Object Information
RGD ID: 2326163
Created: 2010-06-28
Species: All species
Last Modified: 2010-06-28
Status: ACTIVE



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