Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene

Abstract

Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the <i>CCDC88C</i> gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense <i>CCDC88C</i> mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the <i>CCDC88C</i> gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described <i>CCDC88C</i> mutations, we carried out in vitro functional tests. The <i>CCDC88C</i> alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the <i>CCDC88C</i> gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the <i>CCDC88C</i> mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that <i>CCDC88C</i> mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.