In affected members of a large Dutch family with autosomal dominant spinocerebellar ataxia-14 (SCA14; 605361), van de Warrenburg et al. (2003) identified a 353G-A transition in exon 4 of the PRKCG gene, resulting in a gly118-to-asp (G118D) substitution. Two unaffected members also carried the mutation. The G118D mutation occurs in the conserved C1 regulatory domain of the protein.
Verbeek et al. (2005) identified the G118D mutation in 8 additional Dutch patients with SCA14. Three were sibs, and the other 5 were independent referrals. Haplotype analysis indicated a founder effect. Genealogic analysis of these 8 patients and the patients reported by van de Warrenburg et al. (2003) showed that they all derived from a common ancestor from the Dutch province of North Brabant who was born in 1722. Some of the patients exhibited mild extrapyramidal symptoms.
By functional expression studies in COS-7 cells, Verbeek et al. (2005) demonstrated that the G118D mutation increased the intrinsic kinase activity of PRKCG and caused more rapid translocation of the protein to the plasma membrane in response to calcium influx.
