Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse.
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.
Mackenzie
Francesca E
FE
MRC Mammalian Genetics Unit, Harwell OX11 0RD, UK.
Romero
Rosario
R
Williams
Debbie
D
Gillingwater
Thomas
T
Hilton
Helen
H
Dick
Jim
J
Riddoch-Contreras
Joanna
J
Wong
Frances
F
Ireson
Lisa
L
Powles-Glover
Nicola
N
Riley
Genna
G
Underhill
Peter
P
Hough
Tertius
T
Arkell
Ruth
R
Greensmith
Linda
L
Ribchester
Richard R
RR
Blanco
Gonzalo
G
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
C496405:PKD1L2 protein, human; D043562:Receptors, G-Protein-Coupled; D064429:Fatty Acid Synthases