Comparison of two families with and without ataxia harboring novel variants in PRKCG

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant SCA caused by variants of the PRKCG encoding protein kinase C gamma (PKC gamma). Although the toxic gain-of-function mechanism is the main cause of SCA14, its molecular pathophysiology remains unclear. To elucidate the molecular pathogenesis of SCA14, we analyzed two families with the variants inPRKCG. Clinical symptoms and neurological findings of two Japanese families were evaluated by neurologists. Exome sequencing was performed using the BGI platform. GFP-tagged PRKCGs harboring the identified variants were transfected into the HeLa cells, and aggregation of PKC gamma was analyzed using confocal laser microscopy. Solubility of PKC gamma was evaluated by assessing the proportion of insoluble fraction present in1% Triton-X. Patients in family 1 presented with only cerebellar atrophy without ataxia; however, patients in family 2 exhibited cerebellar ataxia, dystonia, and more severe cerebellar atrophy than those in family 1. Exome sequencing identified two novel missense variants of PRKCG:c.171 G > C,p.W57C (family 1), and c.400 T > C,p.C134R (family 2). Both the mutant PKC gamma aggregated in the cytoplasm. Although the solubility of PKC gamma of the C134R variant was lower than that of the wild-type, PKC gamma of W57C retained its solubility. In conclusion, we identified two novel variants of PRKCG. The difference in severity between the two families may be due to the difference in solubility changes observed between the two variants. Decreased solubility of the PKC gamma may play an important role in the pathogenesis of SCA14.

Automated summary

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disorder caused by variants of the PRKCG gene encoding protein kinase C gamma (PKC gamma). In this study, two families with SCA14 were analyzed, and two novel variants of PRKCG were identified. Both variants resulted in aggregation of PKC gamma in the cytoplasm, but the solubility changes differed between the two variants, which may contribute to the difference in severity observed between the two families.