TY  - JOUR
A1  - Aga-Barfknecht, Heja
A1  - Hallahan, Nicole
A1  - Gottmann, Pascal
A1  - Jähnert, Markus
A1  - Osburg, Sophie
A1  - Schulze, Gunnar
A1  - Kamitz, Anne
A1  - Arends, Danny
A1  - Brockmann, Gudrun
A1  - Schallschmidt, Tanja
A1  - Lebek, Sandra
A1  - Chadt, Alexandra
A1  - Al-Hasani, Hadi
A1  - Joost, Hans-Georg
A1  - Schürmann, Annette
A1  - Vogel, Heike
T1  - Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning
JF  - Frontiers in genetics
N2  - Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control.
KW  - type 2 diabetes
KW  - beta-cell loss
KW  - insulin
KW  - positional cloning
KW  - transcriptomics
KW  - haplotype
Y1  - 2020
U6  - https://doi.org/10.3389/fgene.2020.567191
SN  - 1664-8021
VL  - 11
PB  - Frontiers Media
CY  - Lausanne
ER  -