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 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.

CCDC88C variants are associated with focal epilepsy and genotype–phenotype correlation

“…CCDC88C variations were also found in seven cases (15 individuals) with autosomal dominant spinocerebellar ataxia. These were all monoallelic and missense variants 13–19 …”

A Novel c.3636-4 A&gt;G Mutation in the <i>CCDC88C</i> Plays a Causative Role in Familial Spinocerebellar Ataxia

“…Yahia et al [22] reported a case on a Sudanese patient with childhood-onset spastic paraparesis without cerebellar signs caused by a missense mutation (c.1993G > A) in the CCDC88C gene. Boros, F. et al [23] reported a female patient carried a missense mutation (p.R203W) in CCDC88C who developed late-onset ataxia, dysmetria, and intention tremor. Taken together, these findings suggest that the clinical manifestations of SCA40 may be related to race, gene mutation sites, and other factors [24].…”

“…Specifically, this gene mutation causes JNK hyperphosphorylation, upregulates caspase-3 activity, and induces apoptosis [9, 22]. However, studies have also shown that A mutations do not affect c-Jun N-terminal kinase 1 (JNK1) phosphorylation, nor do they trigger apoptosis signals, only a small-scale activation of the JNK pathway [23].…”

Confirmation of the Pathogenetic Role of the CCDC88C Gene in Early‐Onset Pure Spastic Paraplegia

“…5 The p.Arg464Cys identified in our patient is also present in his unaffected mother who, however, has not yet reached the onset age of the majority of patients described with monoallelic CCDC88C variants. 6,7 It is possible that this variant alone is not sufficient to determine an early-onset phenotype and the presence of the second variant may have a role in the early manifestations that we observed in our patient. Had genetic information been available for Yahia et al's 3 case parents, this would help support the CCDC88C variant pathogenetic hypothesis.…”