Abstract
Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder, first described in a Japanese family, showing linkage to chromosome 19q13.4-qter. Recently, mutations have been identified in the PRKCG gene in families with SCA14. The PRKCG gene encodes the protein kinase Cγ (PKCγ), a member of a serine/threonine kinase family involved in signal transduction important for several cellular processes, including cell proliferation and synaptic transmission. To identify the disease-causing mutation in a large group of ataxia patients, we searched for mutations in the PRKCG gene. We ascertained 366 unrelated patients with spinocerebellar ataxia, either pure or with associated features such as epilepsy, mental retardation, seizures, paraplegia, and tremor. A C-to-G transversion in exon 4, resulting in a histidine-to-glutamine change at codon 101 of the PKCγ protein, was identified in patients from a family with slowly progressive pure cerebellar ataxia. Functional studies performed in HEK293 cells transfected with normal or mutant construct showed that this mutation affects PKCγ stability or solubility, verified by time-dependent decreased protein levels in cell culture. In conclusion, the H101Q mutation causes slowly progressive uncomplicated ataxia by interfering with PKCγ stability or solubility, which consequently may cause in either case a decrease in the overall PKCγ-dependent phosphorylation.
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Acknowledgements
We thank all patients and their family members for cooperation, Prof. António Amorim for providing control DNA samples, and Nurse Helena Cardoso for collecting samples. We would also like to thank Dr. S.M. Prescott and Dr. M.K. Topham for kindly providing the PKCγ construct, Prof. Carlos Duarte for the suggestions and careful reading of this manuscript, and Victor Mendes for image technical assistance. This work was supported by research grants POCTI/MGI/34517/00, Financiamento Plurianual de Unidades de Investigação, all from FCT (Fundação para a Ciência e Tecnologia) and FEDER. I.A. and A.I.S. are recipients of scholarships from FCT, Portugal.
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Alonso, I., Costa, C., Gomes, A. et al. A novel H101Q mutation causes PKCγ loss in spinocerebellar ataxia type 14. J Hum Genet 50, 523–529 (2005). https://doi.org/10.1007/s10038-005-0287-z
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DOI: https://doi.org/10.1007/s10038-005-0287-z
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