Spinocerebellar Ataxia Type 14 Caused by a Mutation in Protein Kinase C γ

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Abstract
SPINOCEREBELLAR ataxia type 14 (SCA14) (Online Mendelian Inheritance in Man 605361) is an autosomal dominant neurodegenerative disorder.1 It was first described in a 4-generation Japanese family. Of the 9 patients with SCA14 for whom an age at onset could be determined, the 4 with a late onset (> age 39 years) exhibited pure cerebellar ataxia, whereas the 5 with an early onset (< age 27 years) first showed intermittent axial myoclonus followed by ataxia. Neuroimaging studies revealed that atrophy was confined to the cerebellum. Previously, we reported linkage of the SCA14 locus to a 10.2-cm region between D19S206 and D19S605 on chromosome 19q13.4-qter.1 In 2002, Brkanac et al2 described a 4-generation family of English and Dutch descent in which 14 members had pure SCA in an autosomal dominant pattern. Ten members were available for study and showed a mean age at onset in the third decade, experiencing gait ataxia, dysmetria, dysarthria, abnormal eye movements, and hyperreflexia. Myoclonus was not reported or observed. Linkage analysis mapped the locus to a 22-cm region on chromosome 19q13.4-qter that encompassed the locus for SCA14. Recently, 3 different nonconservative missense mutations in exon 4 of the protein kinase C γ gene (PRKCG) (National Center for Biotechnology Information accession No. 002739), which is located between D19S927 and D19S418 on 19q13.4, were reported in the family studied in the linkage analysis, an additional family with SCA, and a sporadic case from the United States.2,3 These affected individuals displayed pure ataxia, and none had myoclonus. Because of the difference in phenotype, it was not known whether mutations in a different part of the PRKCG gene were associated with SCA14 and myoclonus or whether 2 distinct diseases were mapping to the same large genomic region with at least 150 genes in the minimal shared area. Our study was performed to address this question and to investigate the prevalence of PRKCG mutations in Japanese patients with autosomal dominant SCA.

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