title: A novel H101Q mutation causes PKCgamma loss in spinocerebellar ataxia type 14.
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 Cgamma (PKCgamma), 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 PKCgamma 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 PKCgamma 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 PKCgamma stability or solubility, which consequently may cause in either case a decrease in the overall PKCgamma-dependent phosphorylation.
authors.affiliation: UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: Serviço de Neurologia, Hospital Fernando da Fonseca, Amadora, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Costa
authors.affiliation: Centro de Neurociências de Coimbra, University of Coimbra, Coimbra, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Gomes
authors.affiliation: UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Ferro
authors.affiliation: UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Seixas
authors.affiliation: Hospital de São Sebastião, Feira, Portugal.
authors.forename: Sérgio
authors.initials: S
authors.lastname: Silva
authors.affiliation: Hospital de São Sebastião, Feira, Portugal.
authors.forename: Vitor Tedim
authors.initials: VT
authors.lastname: Cruz
authors.affiliation: Hospital de São Sebastião, Feira, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.affiliation: UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.affiliation: UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal. isilveir@ibmc.up.pt.
authors.forename: Isabel
authors.initials: I
authors.lastname: Silveira
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D003062:Codon; D006801:Humans; D017354:Point Mutation; D011493:Protein Kinase C / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000201:enzymology / Q000235:genetics*
chemical_list: D003062:Codon; C087857:protein kinase C gamma; D011493:Protein Kinase C