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Brain Advance Access originally published online on December 23, 2004
Brain 2005 128(2):436-442; doi:10.1093/brain/awh378
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Brain Vol. 128 No. 2 © Guarantors of Brain 2004; all rights reserved

Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting

D. S. Verbeek1,2,*, M. A. Knight1,*, G. G. Harmison1, K. H. Fischbeck1 and B. W. Howell1

1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA, and 2 Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, Netherlands

Correspondence to: B. Howell, Neurogenetics Branch, NINDS/NIH, 35 Convent Drive, Building 35 Rm 2A116, Bethesda, MD 20892, USA E-mail: howellb{at}ninds.nih.gov

The protein kinase C gamma (PKC{gamma}) gene is mutated in spinocerebellar ataxia type 14 (SCA14). In this study, we investigated the effects of two SCA14 missense mutations, G118D and C150F, on PKC{gamma} function. We found that these mutations increase the intrinsic activity of PKC{gamma}. Direct visualization of labelled PKC{gamma} in living cells demonstrates that the mutant protein translocates more rapidly to selected regions of the plasma membrane in response to Ca2+ influx. These results point to specific alterations in mutant PKC{gamma} function that could lead to the selective neuronal degeneration of SCA14.

* These authors contributed equally to this work


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