title: R659S mutation of gammaPKC is susceptible to cell death: implication of this mutation/polymorphism in the pathogenesis of retinitis pigmentosa.
abstract: It has been reported that mutations of gammaPKC cause hereditary spinocerebellar atrophy type 14 (SCA14). Our recent study has revealed that the SCA14 mutant gammaPKC is susceptible to aggregation and causes cell death. Among mutations/polymorphisms of gammaPKC, the R659S mutation was firstly segregated from families with hereditary retinitis pigmentosa type 11 (RP11). Although more reliable etiological mutations of RP11 were subsequently discovered in a human homologue of yeast pre-mRNA splicing gene (PRP31), the role of this R659S missense change in the pathogenicity of RP11 is still controversial. In this study, we overexpressed R659S gammaPKC in CHO cells and characterized the properties of this mutant protein. We found that R659S gammaPKC more prominently induced cell death than did wild-type. This mutant gammaPKC had higher basal activity than wild-type, however, no difference was found in the extent of aggregation and insolubility to detergent between R659S mutant and wild-type. These results suggest that the R659S mutation is susceptible to neuronal death and is involved in the pathogenesis of neurodegenerative diseases, including RP11.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Naoko
authors.initials: N
authors.lastname: Adachi
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.forename: Hiromu K
authors.initials: HK
authors.lastname: Mishima
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D016923:Cell Death / Q000235:genetics; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003902:Detergents / Q000494:pharmacology; D004789:Enzyme Activation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D049452:Green Fluorescent Proteins; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011493:Protein Kinase C / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D012995:Solubility
chemical_list: D003902:Detergents; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; C087857:protein kinase C gamma; D011493:Protein Kinase C