Human Molecular Genetics Advance Access originally published online on July 4, 2009
Human Molecular Genetics 2009 18(19):3553-3566; doi:10.1093/hmg/ddp304
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Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse
1 MRC Mammalian Genetics Unit, Harwell OX11 0RD, UK, 2 Centre for Neuroscience Research, University of Edinburgh, 1 George Square, Edinburgh EH9 1QH, UK, 3 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1E 6BT, UK and 4 Research School of Biological Sciences, The Australian National University, GPO Box 475, Canberra ACT 2601, Australia
* To whom correspondence should be addressed. Tel: +44 1235841072; Fax: +44 1235841000; Email: g.blanco{at}har.mrc.ac.uk
Received May 7, 2009; Accepted July 1, 2009
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.