Objective: To investigate the association between rare deleterious CCDC88C variants and PD.

Background: SCA40 is a rare form of spinocerebellar ataxia caused by heterozygous mutations in CCDC88C. Besides ataxia, parkinsonism was also reported in some patients with SCA40. Our routine genetic study of patients with Parkinson’s disease (PD) identified 2 siblings with PD who both carried a variant reported as a pathogenic mutation in SCA40 patients. Therefore, we speculated that CCDC88C is likely associated with PD.

Method: Segregation analyses and vitro functional experiments were performed in 2 reported pathogenic variants (p.R319Q, p.R464H) and one novel variant (p.Q686R) absent from public genetic variation databases, including protein expression level and cell JNK/caspase3 pathway activation by Western-blot, subcellular localization by immunofluorescence, and apoptosis level by flow cytometry. Gene-based burden analyses were performed on two cohorts. One cohort consisted of 403 PD patients from our next-generation sequencing database and 13587 normal controls from ChinaMap (10588) and Nyvwa (2999) databases respectively. The other included 606 PD patients from Parkinson’s Progression Markers Initiative (PPMI) database and 141456 normal controls from gnomAD (v2.1.1) database.

Results: Genotype-phenotype analyses revealed that p.R319Q, p.R464H, and p.Q686R co-segregated in 4 families. Functional experiments in HEK293T cells demonstrated that p.R319Q, p.R464H, and p.Q686R didn’t affect the expression level and localization of the CCDC88C protein and didn’t activate JNK, but induced caspase 3 cleavage and triggered apoptosis. In the Chinese PD cohort, a total of 9 rare deleterious variants were identified, of which, p.R319Q and p.R464H were reported as pathogenic mutations in SCA40 patients. Burden analyses did not reveal any significant enrichment of rare deleterious CCDC88C variants in both Chinese (p = 0.443; OR = 0.705; 95% confident interval = 0.475-1.109) and another population cohort (p = 0.2917; OR = 1.288; 95% confident interval = 0.772-2.023).

Conclusion: The association between rare deleterious CCDC88C variants and PD is uncertain. Consequently, more thorough studies are required to illustrate the association between rare deleterious CCDC88C variants and PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-and-functional-analysis-of-ccdc88c-mutations-in-patients-with-parkinsons-disease/