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

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dc.contributor.authorPeiris, H.
dc.contributor.authorDuffield, M.D.
dc.contributor.authorFadista, J.
dc.contributor.authorJessup, C.F.
dc.contributor.authorKashmir, V.
dc.contributor.authorGenders, A.J.
dc.contributor.authorMcGee, S.L.
dc.contributor.authorMartin, A.M.
dc.contributor.authorSaiedi, M.
dc.contributor.authorMorton, N.
dc.contributor.authorCarter, R.
dc.contributor.authorCousin, M.A.
dc.contributor.authorKokotos, A.C.
dc.contributor.authorOskolkov, N.
dc.contributor.authorVolkov, P.
dc.contributor.authorHough, T.A.
dc.contributor.authorFisher, E.M.C.
dc.contributor.authorTybulewicz, V.L.J.
dc.contributor.authorBusciglio, J.
dc.contributor.authorCoskun, P.E.
dc.contributor.authoret al.
dc.contributor.editorScott, H.S.
dc.date.issued2016
dc.description.abstractType 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.
dc.description.statementofresponsibilityHeshan 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
dc.identifier.citationPLoS Genetics, 2016; 12(5):e1006033-1-e1006033-24
dc.identifier.doi10.1371/journal.pgen.1006033
dc.identifier.issn1553-7390
dc.identifier.issn1553-7404
dc.identifier.orcidJessup, C.F. [0000-0003-1184-6653]
dc.identifier.urihttp://hdl.handle.net/2440/101735
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1008816
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1088737
dc.relation.granthttp://purl.org/au-research/grants/arc/FT0990901
dc.rightsCopyright: © 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
dc.source.urihttps://doi.org/10.1371/journal.pgen.1006033
dc.subjectChromosomes, Human, Pair 21
dc.subjectMitochondria
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDown Syndrome
dc.subjectDiabetes Mellitus, Type 2
dc.subjectHyperglycemia
dc.subjectAneuploidy
dc.subjectInsulin
dc.subjectGlucose
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectCalcium-Binding Proteins
dc.subjectMuscle Proteins
dc.subjectAdenosine Triphosphate
dc.subjectProtein Biosynthesis
dc.subjectGene Expression Regulation
dc.subjectInsulin-Secreting Cells
dc.titleA syntenic cross species aneuploidy genetic screen links RCAN1 expression to β-Cell mitochondrial dysfunction in type 2 diabetes
dc.title.alternativeA syntenic cross species aneuploidy genetic screen links RCAN1 expression to beta-cell mitochondrial dysfunction in type 2 diabetes
dc.typeJournal article
pubs.publication-statusPublished

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