E96V Mutation in the Kdelr3 Gene Is Associated with Type 2 Diabetes Susceptibility in Obese NZO Mice

• Published in: International journal of molecular sciences Vol. 24; no. 1; p. 845
• Main Authors: Altenhofen, Delsi, Khuong, Jenny Minh-An, Kuhn, Tanja, Lebek, Sandra, Görigk, Sarah, Kaiser, Katharina, Binsch, Christian, Griess, Kerstin, Knebel, Birgit, Belgardt, Bengt-Frederik, Cames, Sandra, Eickelschulte, Samaneh, Stermann, Torben, Rasche, Axel, Herwig, Ralf, Weiss, Jürgen, Vogel, Heike, Schürmann, Annette, Chadt, Alexandra, Al-Hasani, Hadi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 03-01-2023; MDPI AG
• Subjects: Animals; Diabetes Mellitus, Type 2 - genetics; endoplasmic reticulum stress; Genetic Predisposition to Disease; Insulin - metabolism; insulin secretion; Insulin-Secreting Cells - metabolism; Mice; Mice, Inbred C3H; Mice, Obese; Obesity - genetics; pancreatic islet function; positional cloning; Receptors, Peptide - genetics; type 2 diabetes susceptibility; positional cloning; insulin secretion; type 2 diabetes susceptibility; endoplasmic reticulum stress; pancreatic islet function
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24010845

Type 2 diabetes (T2D) represents a multifactorial metabolic disease with a strong genetic predisposition. Despite elaborate efforts in identifying the genetic variants determining individual susceptibility towards T2D, the majority of genetic factors driving disease development remain poorly understood. With the aim to identify novel T2D risk genes we previously generated an N2 outcross population using the two inbred mouse strains New Zealand obese (NZO) and C3HeB/FeJ (C3H). A linkage study performed in this population led to the identification of the novel T2D-associated quantitative trait locus (QTL)
(NZO blood glucose on chromosome 15, Logarithm of odds (LOD) 6.6). In this study we used a combined approach of positional cloning, gene expression analyses and in silico predictions of DNA polymorphism on gene/protein function to dissect the genetic variants linking
to the development of T2D. Moreover, we have generated congenic strains that associated the distal sublocus of
to mechanisms altering pancreatic beta cell function. In this sublocus,
,
and
were nominated as potential causative genes associated with the
driven effects. Moreover, a putative mutation in the
gene from NZO was identified, negatively influencing adaptive responses associated with pancreatic beta cell death and induction of endoplasmic reticulum stress. Importantly, knockdown of
in cultured Min6 beta cells altered insulin granules maturation and pro-insulin levels, pointing towards a crucial role of this gene in islets function and T2D susceptibility.