title: Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse.
abstract: Following a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosourea-induced 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.
authors: MRC Mammalian Genetics Unit, Harwell OX11 0RD, UK.
authors: Francesca E
authors: FE
authors: Mackenzie
authors: Rosario
authors: R
authors: Romero
authors: Debbie
authors: D
authors: Williams
authors: Thomas
authors: T
authors: Gillingwater
authors: Helen
authors: H
authors: Hilton
authors: Jim
authors: J
authors: Dick
authors: Joanna
authors: J
authors: Riddoch-Contreras
authors: Frances
authors: F
authors: Wong
authors: Lisa
authors: L
authors: Ireson
authors: Nicola
authors: N
authors: Powles-Glover
authors: Genna
authors: G
authors: Riley
authors: Peter
authors: P
authors: Underhill
authors: Tertius
authors: T
authors: Hough
authors: Ruth
authors: R
authors: Arkell
authors: Linda
authors: L
authors: Greensmith
authors: Richard R
authors: RR
authors: Ribchester
authors: Gonzalo
authors: G
authors: Blanco
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C496405:PKD1L2 protein, human; D043562:Receptors, G-Protein-Coupled; D064429:Fatty Acid Synthases