A novel H101Q mutation causes PKCgamma loss in spinocerebellar ataxia type 14.
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.
Alonso
Isabel
I
UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
Costa
Cristina
C
Serviço de Neurologia, Hospital Fernando da Fonseca, Amadora, Portugal.
Gomes
André
A
Centro de Neurociências de Coimbra, University of Coimbra, Coimbra, Portugal.
Ferro
Anabela
A
UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
Seixas
Ana I
AI
UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
Silva
Sérgio
S
Hospital de São Sebastião, Feira, Portugal.
Cruz
Vitor Tedim
VT
Hospital de São Sebastião, Feira, Portugal.
Coutinho
Paula
P
Hospital de São Sebastião, Feira, Portugal.
Sequeiros
Jorge
J
UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal.|ICBAS, University of Porto, Porto, Portugal.
Silveira
Isabel
I
UnIGENe, IBMC, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal. isilveir@ibmc.up.pt.
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*
D003062:Codon; C087857:protein kinase C gamma; D011493:Protein Kinase C