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Hum Mol Genet ; 18(19): 3553-66, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19578180

RESUMO

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.


Assuntos
Doenças Neuromusculares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulação para Cima , Animais , Células Cultivadas , Modelos Animais de Doenças , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Células HeLa , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Mutação , Doenças Neuromusculares/genética , Ligação Proteica , Receptores Acoplados a Proteínas G/genética
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