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Science 329 (5990): 458-461

Copyright © 2010 by the American Association for the Advancement of Science

Muscle Dysfunction Caused by a KATP Channel Mutation in Neonatal Diabetes Is Neuronal in Origin

Rebecca H. Clark,1 James S. McTaggart,1,* Richard Webster,2,* Roope Mannikko,1,* Michaela Iberl,1 Xiu Li Sim,1 Patrik Rorsman,3 Maike Glitsch,1 David Beeson,2 Frances M. Ashcroft1,{dagger}

Abstract: Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)–sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic β-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59->Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.

1 Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
3 Oxford Centre for Diabetes Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: frances.ashcroft{at}dpag.ox.ac.uk


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