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Type: Journal article
Title: A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-Cell mitochondrial dysfunction in type 2 diabetes
Other Titles: A syntenic cross species aneuploidy genetic screen links RCAN1 expression to beta-cell mitochondrial dysfunction in type 2 diabetes
Author: Peiris, H.
Duffield, M.
Fadista, J.
Jessup, C.
Kashmir, V.
Genders, A.
McGee, S.
Martin, A.
Saiedi, M.
Morton, N.
Carter, R.
Cousin, M.
Kokotos, A.
Oskolkov, N.
Volkov, P.
Hough, T.
Fisher, E.
Tybulewicz, V.
Busciglio, J.
Coskun, P.
et al.
Citation: PLoS Genetics, 2016; 12(5):e1006033-1-e1006033-24
Publisher: Public Library of Science
Issue Date: 2016
ISSN: 1553-7390
Statement of
Heshan Peiris, Michael D. Duffield, Joao Fadista, Claire F. Jessup, Vinder Kashmir, Amanda J. Genders, Sean L. McGee, Alyce M. Martin, Madiha Saiedi, Nicholas Morton, Roderick Carter, Michael A. Cousin, Alexandros C. Kokotos, Nikolay Oskolkov, Petr Volkov, Tertius A. Hough, Elizabeth M. C. Fisher, Victor L. J. Tybulewicz, Jorge Busciglio, Pinar E. Coskun, Ann Becker, Pavel V. Belichenko, William C. Mobley, Michael T. Ryan, Jeng Yie Chan, D. Ross Laybutt, P. Toby Coates, Sijun Yang, Charlotte Ling, Leif Groop, Melanie A. Pritchard, Damien J. Keating
Abstract: Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.
Keywords: Chromosomes, Human, Pair 21; Mitochondria; Animals; Humans; Mice; Down Syndrome; Diabetes Mellitus, Type 2; Hyperglycemia; Aneuploidy; Insulin; Glucose; Intracellular Signaling Peptides and Proteins; Muscle Proteins; Adenosine Triphosphate; Protein Biosynthesis; Gene Expression Regulation; Insulin-Secreting Cells
Rights: Copyright: © 2016 Peiris et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
RMID: 0030048256
DOI: 10.1371/journal.pgen.1006033
Grant ID:
Appears in Collections:Medical Sciences publications

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