Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene

Publication date: Available online 31 May 2019Source: Molecular and Cellular NeuroscienceAuthor(s): Toshihiko Shirafuji, Haruo Shimazaki, Tatsuhiro Miyagi, Takehiko Ueyama, Naoko Adachi, Shigeru Tanaka, Izumi Hide, Naoaki Saito, Norio SakaiAbstractSpinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia with myoclonus, dystonia, spasticity, and rigidity. Although missense mutations and a deletion mutation have been found in the protein kinase C gamma (PRKCG) gene encoding protein kinase C γ (PKCγ) in SCA14 families, a nonsense mutation has not been reported. The patho-mechanisms underlying SCA14 remain poorly understood. However, gain-of-function mechanisms and loss-of-function mechanisms, but not dominant negative mechanisms, were reported the patho-mechanism of SCA14. We identified the c.226C>T mutation of PRKCG, which caused the p.R76X in PKCγ by whole-exome sequencing in patients presenting cerebellar atrophy with cognitive and hearing impairment. To investigate the patho-mechanism of our case, we studied aggregation formation, cell death, and PKC inhibitory effect by confocal microscopy, western blotting with cleaved caspase 3, and pSer PKC motif antibodies, respectively.PKCγ(R76X)-GFP have aggregations the same as wild-type (WT) PKCγ-GFP. The PKCγ(R76X)-GFP inhibited PKC phosphorylation activity more than GFP alone. It also induced more apoptosis in COS7 and SH-SY5Y cells compared to WT-PKCγ-GFP...

Source: Molecular and Cellular Neuroscience - June 1, 2019 Category: Neuroscience Source Type: research