Human Molecular Genetics Advance Access originally published online on June 26, 2009
Human Molecular Genetics 2009 18(19):3533-3543; doi:10.1093/hmg/ddp298
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Protein kinase C
, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin
1 Department of Neurology, 2 Department of Pathology and 3 Radioisotope Research Center, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan and 4 Department of Neurology, Sumitomo Hospital, Osaka, Japan
* To whom correspondence should be addressed. Tel: +81 744298860; Fax: +81 744246065; Email: hirano_makito{at}yahoo.co.jp or mhirano{at}naramed-u.ac.jp
Received March 24, 2009; Accepted June 24, 2009
Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C
(PKC). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with increased kinase activity. Notably, one patient with a severe phenotype is the first homozygote for the mutation causing SCA14. We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (APTX), a DNA repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant PKC, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin 
, a nuclear import adaptor. Decreased nuclear APTX increased oxidative stress-induced DNA damage and cell death. Phosphorylation-resistant APTX, kinase inhibitors, and antioxidants may be therapeutic options for SCA14.