Upregulation of PKD1L2 Provokes a Complex Neuromuscular Disease in the Mouse

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2009 Jul 7

PMID 19578180

Citations 9

Authors

Francesca E Mackenzie

Rosario Romero

Debbie Williams

Thomas Gillingwater

Helen Hilton

Jim Dick

Joanna Riddoch-Contreras

Frances Wong

Lisa Ireson

Nicola Powles-Glover

Genna Riley

Peter Underhill

Tertius Hough

Ruth Arkell

Linda Greensmith

Richard R Ribchester

Gonzalo Blanco

Affiliations

Soon will be listed here.

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.

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