RGD Reference Report - GENDER-SPECIFIC GENETIC DISSECTION OF DIABETES IN A RODENT MODEL IDENTIFIES ICA1 AND NDUFA4 AS MAJOR CANDIDATE GENES. - Rat Genome Database

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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.
RGD ID: 2326163
Pubmed: PMID:20530722   (View Abstract at PubMed)
DOI: DOI:10.1152/physiolgenomics.00042.2010   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Diabetes Mellitus  IAGP 2326163; 2326163; 2326163; 2326163 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased circulating glucose level  IAGP 2326163compared to CDS/Ygl on diabetogenic dietRGD 
decreased circulating insulin level  IDA 2326163; 2326163; 2326163 RGD 
decreased pancreas weight  IDA 2326163; 2326163; 2326163 RGD 
increased circulating glucose level  IAGP 2326163compared to CDR/YglRGD 
increased circulating glucose level  IDA 2326163; 2326163; 2326163 RGD 
increased pancreas weight  IAGP 2326163compared to CDS/Ygl on diabetogenic dietRGD 
increased pancreas weight  IDA 2326163 RGD 
Objects Annotated

QTLs
Gluco61  (Glucose level QTL 61)
Gluco62  (Glucose level QTL 62)
Gluco63  (Glucose level QTL 63)
Pancm3  (Pancreatic morphology QTL 3)

Strains
CDR/Ygl  (NA)
CDS-Chr 4CDR/Ygl  (NA)
CDS/Ygl  (Cohen diabetic-sensitive rat)

Objects referenced in this article
QTL Gluco32 Glucose level QTL 32 Rattus norvegicus
QTL Gluco33 Glucose level QTL 33 Rattus norvegicus
QTL Gluco34 Glucose level QTL 34 Rattus norvegicus

Additional Information