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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Mackenzie FE,Romero R,Williams D,Gillingwater T,Hilton H,Dick J,Riddoch-Contreras J,Wong F,Ireson L,Powles-Glover N,Riley G,Underhill P,Hough T,Arkell R,Greensmith L,Ribchester RR,Blanco Gdoi
10.1093/hmg/ddp304subject
Has Abstractpub_date
2009-10-01 00:00:00pages
3553-66issue
19eissn
0964-6906issn
1460-2083pii
ddp304journal_volume
18pub_type
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