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

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

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 underst...

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Bibliographic Details
Main Authors: Delsi Altenhofen, Jenny Minh-An Khuong, Tanja Kuhn, Sandra Lebek, Sarah Görigk, Katharina Kaiser, Christian Binsch, Kerstin Griess, Birgit Knebel, Bengt-Frederik Belgardt, Sandra Cames, Samaneh Eickelschulte, Torben Stermann, Axel Rasche, Ralf Herwig, Jürgen Weiss, Heike Vogel, Annette Schürmann, Alexandra Chadt, Hadi Al-Hasani
Format: Article
Language:English
Published: MDPI AG 2023-01-01
Series:International Journal of Molecular Sciences
Subjects:
type 2 diabetes susceptibility
pancreatic islet function
insulin secretion
positional cloning
endoplasmic reticulum stress
Online Access:https://www.mdpi.com/1422-0067/24/1/845
Description
Summary: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) <i>Nbg15</i> (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 <i>Nbg15</i> to the development of T2D. Moreover, we have generated congenic strains that associated the distal sublocus of <i>Nbg15</i> to mechanisms altering pancreatic beta cell function. In this sublocus, <i>Cbx6</i>, <i>Fam135b</i> and <i>Kdelr3</i> were nominated as potential causative genes associated with the <i>Nbg15</i> driven effects. Moreover, a putative mutation in the <i>Kdelr3</i> gene from NZO was identified, negatively influencing adaptive responses associated with pancreatic beta cell death and induction of endoplasmic reticulum stress. Importantly, knockdown of <i>Kdelr3</i> 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.
ISSN:1661-6596
1422-0067

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