Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically
and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C
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 CCDC88C
mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C
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 CCDC88C mutations, we carried out in vitro functional tests.
The CCDC88C 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 CCDC88C 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 CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore,
we propose that CCDC88C mutations may exert their effects through different and possibly
in much broader, yet unexplored, biological processes.
