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Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse

Mackenzie, Francesca E; Romero, Rosario; Williams, Debbie; Gillingwater, Thomas; Hilton, Helen; Dick, Jim; Riddoch-Contreras, Joanna; Wong, Frances; Ireson, Lisa; Powles-Glover, Nicola; Riley, Genna; Underhill, Peter; Hough, Tertius; Arkell, Ruth; Greensmith, Linda; Ribchester, Richard R; Blanco, Gonzalo

Description

Following a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosoureainduced mouse mutant with muscle atrophy. Genetic and biochemical evidence shows that upregulation of the novel, uncharacterized transient receptor potential polycystic (TRPP) channel PKD1L2 (polycystic kidney disease gene 1-like 2) underlies this disease. Ostes mice suffer from chronic neuromuscular impairments including neuromuscular junction degeneration, polyneuronal innervation and...[Show more]

dc.contributor.authorMackenzie, Francesca E
dc.contributor.authorRomero, Rosario
dc.contributor.authorWilliams, Debbie
dc.contributor.authorGillingwater, Thomas
dc.contributor.authorHilton, Helen
dc.contributor.authorDick, Jim
dc.contributor.authorRiddoch-Contreras, Joanna
dc.contributor.authorWong, Frances
dc.contributor.authorIreson, Lisa
dc.contributor.authorPowles-Glover, Nicola
dc.contributor.authorRiley, Genna
dc.contributor.authorUnderhill, Peter
dc.contributor.authorHough, Tertius
dc.contributor.authorArkell, Ruth
dc.contributor.authorGreensmith, Linda
dc.contributor.authorRibchester, Richard R
dc.contributor.authorBlanco, Gonzalo
dc.date.accessioned2015-12-10T23:07:33Z
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/1885/62930
dc.description.abstractFollowing a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosoureainduced mouse mutant with muscle atrophy. Genetic and biochemical evidence shows that upregulation of the novel, uncharacterized transient receptor potential polycystic (TRPP) channel PKD1L2 (polycystic kidney disease gene 1-like 2) underlies this disease. Ostes mice suffer from chronic neuromuscular impairments including neuromuscular junction degeneration, polyneuronal innervation and myopathy. Ectopic expression of PKD1L2 in transgenic mice reproduced the ostes myopathic changes and, indeed, caused severe muscle atrophy in Tg(Pkd1l2)/Tg(Pkd1l2) mice. Moreover, double-heterozygous mice (ostes/+, Tg(Pkd1l2)/0) suffer from myopathic changes more profound than each heterozygote, indicating positive correlation between PKD1L2 levels and disease severity. We show that, in vivo, PKD1L2 primarily associates with endogenous fatty acid synthase in normal skeletal muscle, and these proteins co-localize to costameric regions of the muscle fibre. In diseased ostes/ostes muscle, both proteins are upregulated, and ostes/ostes mice show signs of abnormal lipid metabolism. This work shows the first role for a TRPP channel in neuromuscular integrity and disease.
dc.publisherOxford University Press
dc.sourceHuman Molecular Genetics
dc.subjectKeywords: fatty acid synthase; G protein coupled receptor; PKD1L2 protein, human; animal; article; cell culture; disease model; female; genetics; HeLa cell; human; infant; male; metabolism; mouse; mutation; neuromuscular disease; protein binding; skeletal muscle; t
dc.titleUpregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume18
dc.date.issued2009
local.identifier.absfor060403 - Developmental Genetics (incl. Sex Determination)
local.identifier.ariespublicationu9204316xPUB751
local.type.statusPublished Version
local.contributor.affiliationMackenzie, Francesca E, MRC Mammalian Genetics Unit
local.contributor.affiliationRomero, Rosario, MRC Mammalian Genetics Unit
local.contributor.affiliationWilliams, Debbie, MRC Mammalian Genetics Unit
local.contributor.affiliationGillingwater, Thomas, University of Edinburgh
local.contributor.affiliationHilton, Helen, MRC Mammalian Genetics Unit
local.contributor.affiliationDick, Jim, University of London
local.contributor.affiliationRiddoch-Contreras, Joanna, University of London
local.contributor.affiliationWong, Frances, MRC Mammalian Genetics Unit
local.contributor.affiliationIreson, Lisa, MRC Mammalian Genetics Unit
local.contributor.affiliationPowles-Glover, Nicola, MRC Harwell
local.contributor.affiliationRiley, Genna, MRC Mammalian Genetics Unit
local.contributor.affiliationUnderhill, Peter, MRC Mammalian Genetics Unit
local.contributor.affiliationHough, Tertius, MRC Mammalian Genetics Unit
local.contributor.affiliationArkell, Ruth, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationGreensmith, Linda, University of London
local.contributor.affiliationRibchester, Richard R, University of Edinburgh
local.contributor.affiliationBlanco, Gonzalo, MRC Mammalian Genetics Unit
local.description.embargo2037-12-31
local.bibliographicCitation.issue19
local.bibliographicCitation.startpage3553
local.bibliographicCitation.lastpage3566
local.identifier.doi10.1093/hmg/ddp304
dc.date.updated2016-02-24T11:53:54Z
local.identifier.scopusID2-s2.0-70350787052
local.identifier.thomsonID000270707900003
CollectionsANU Research Publications

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