Identification of two novel candidate genes for insulin secretion by comparative genomics of multiple backcross populations
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ABSTRACT: To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetes-susceptible New Zealand Obese (NZO) with the two lean mouse strains 129P2 and C3H/FeJ. Subsequent whole-genome linkage scan revealed 36 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose (12 cM, LOD 13.3) and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Cdp7prox) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is unique for the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains (RCS) and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb) we used a combined approach of haplotype- and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared as the most likely target tissue for the QTL. Only the two genes Potassium-transporting ATPase alpha chain 1 (Atp4a) and Ribonuclease P protein subunit p29 (Pop4) fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to a decreased glucose-stimulated insulin secretion (GSIS), indicating a stimulating role of both genes in insulin secretion, thereby likely contributing to the phenotype linked to Cdp7prox. In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility genes and thus has proven to be a powerful tool for the discovery of novel disease genes.
ORGANISM(S): Mus musculus
PROVIDER: GSE117553 | GEO | 2019/05/27
REPOSITORIES: GEO
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