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A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-cell mitochondrial dysfunction in Type 2 diabetes

Peiris, Heshan, Duffield, Michael D., Fadista, Joao, Jessup, Claire F., Kashmir, Vinder, Genders, Amanda J., McGee, Sean L., Martin, Alyce M., Saiedi, Madiha, Morton, Nicholas, Carter, Roderick, Cousin, Michael A., Kokotos, Alexandros C., Oskolkov, Nikolay, Volkov, Petr, Hough, Tertius A., Fisher, Elizabeth M. C., Tybulewicz, Victor L. J., Busciglio, Jorge, Coskun, Pinar E., Becker, Ann, Belichenko, Pavel V., Mobley, William C., Ryan, Michael T., Chan, Jeng Yie, Laybutt, D. Ross, Coates, P. Toby, Yang, Sijun, Ling, Charlotte, Groop, Leif, Pritchard, Melanie A. and Keating, Damien J. 2016, A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-cell mitochondrial dysfunction in Type 2 diabetes, PLoS genetics, vol. 12, no. 5, pp. 1-24, doi: 10.1371/journal.pgen.1006033.

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Title A syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-cell mitochondrial dysfunction in Type 2 diabetes
Author(s) Peiris, Heshan
Duffield, Michael D.
Fadista, Joao
Jessup, Claire F.
Kashmir, Vinder
Genders, Amanda J.
McGee, Sean L.
Martin, Alyce M.
Saiedi, Madiha
Morton, Nicholas
Carter, Roderick
Cousin, Michael A.
Kokotos, Alexandros C.
Oskolkov, Nikolay
Volkov, Petr
Hough, Tertius A.
Fisher, Elizabeth M. C.
Tybulewicz, Victor L. J.
Busciglio, Jorge
Coskun, Pinar E.
Becker, Ann
Belichenko, Pavel V.
Mobley, William C.
Ryan, Michael T.
Chan, Jeng Yie
Laybutt, D. Ross
Coates, P. Toby
Yang, Sijun
Ling, Charlotte
Groop, Leif
Pritchard, Melanie A.
Keating, Damien J.
Journal name PLoS genetics
Volume number 12
Issue number 5
Start page 1
End page 24
Total pages 24
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2016-05-19
ISSN 1553-7404
Summary 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.
Language eng
DOI 10.1371/journal.pgen.1006033
Field of Research 060499 Genetics not elsewhere classified
0604 Genetics
Socio Economic Objective 920499 Public Health (excl. Specific Population Health) not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30083769

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.