Parkinson's disease (PD) is the second most common neurodegenerative disorder and is caused by an interaction of aging with environmental and genetic factors. The genetics of PD have been extensively studied over the past 20 years. However, the common monogenetic PD accounts for only 30% of familial and 3–5% of sporadic cases (1). One recent meta-analysis of genome-wide association studies (GWASs) on PD revealed 90 notable independent genome-wide risk variants (2). These variants only contribute to 16–36% of the heritable risk of PD. Considerable risk of pathogenic variants associated with the progression of PD has yet to be discovered.

Recently, Lin et al. reported that the variants of the ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene were linked to autosomal dominant parkinsonism with polyneuropathy (3, 4). After the c.941A > C (p.Y314S) variant was identified in an index family (3), c.931A > C (p.I311L) and the allele with concomitant c.70-1G4A and c.73_73insG (p.A25Gfs^*2) variants were further identified in two other families with PD in this study. The affected individuals presented with asymmetrical tremor predominant parkinsonism and had a mean onset age of 57.5 years (range: 42–69 years). Images from Tc-99m TRODAT single-photon emission computed tomography indicated asymmetric loss of the dopamine transporter. Nerve conduction studies revealed axonal-type predominant sensorimotor polyneuropathy. All patients exhibited satisfactory responses to levodopa (4).

Mitochondrial dysfunction is a key in the pathogenesis of idiopathic and monogenetic PD (5). PD-associated genes, such as PRKN, PINK1, and DJ-1, are directly involved in mitochondrial functions. Although LRRK2, SNCA, and GBA indirectly affect the electron transport chain through the regulation of lysosomal functions, lipid metabolism, and protein aggregation (6). UQCRC1 is a core subunit of the mitochondrial respiratory chain complex III (7). UQCRC1 p.Y314S may disrupt the activity of mitochondrial respiratory chain complex III in the neurons and may be associated with impaired locomotion, dopaminergic neuronal loss, and peripheral nerve degeneration (4). The knockout of UQCRC1 also affects brain ischemic tolerance and is involved in apoptotic neurodegeneration (8, 9).

As UQCRC1 p.Y314S was first reported among a Taiwanese family, this study investigated the pathogenicity of UQCRC1 variants in a Taiwanese cohort of patients with early-onset or familial PD.

Supplementary Table 3 summarizes the UQCRC1 variants identified in our study. No previously reported potentially pathogenic variants were identified in our patients. Three missense variants (c.643G > C, p.D215H; c.800C > G, p.P267R, and c.923A > G, p.N308S) were identified (Table 1). Two of those variants (p.D215H and p.P267R) exhibited a relatively high allele frequency (MAF > 3%) among East Asian and Taiwanese populations. Less than half the in silico tools indicated a pathogenic consequence in the three missense variants. The in silico pathogenicity predictions are detailed in Supplementary Table 4. Seven rare variants (with MAF <0.1% in all databases, if available) were identified, including four intron variants, two non-coding transcript variants, and one synonymous variant (Supplementary Tables 5, 6). No association of the variants with changes in the splice site change was indicated; in addition, the variants were not strongly conserved across species. Pathogenicity was classified according to the ACMG criteria, as displayed in Table 1, Supplementary Tables 5, 6.

Among the UQCRC1 variants identified in this study, the allele frequencies of only 12 variants were reported in the Taiwan Biobank database. The prevalence of c.297 + 21C > T was higher among our participants than among the enrollees of the Taiwan Biobank database (p = 0.025), but this difference was non-significant after the Bonferroni correction was applied (Supplementary Table 3). The frequencies of carriers of the remaining 11 variants identified in both groups were similar.

In this study, we performed a comprehensive mutational screening of UQCRC1 in a Taiwanese cohort of patients with EOPD and FPD. We identified no pathogenic variants potential associated with the risk of PD.

Although we identified three missense variants (c.643G > C, p.D215H; c.800C > G, p.P267R, and c.923A > G, p.N308S) among our participants, their pathogenicity was low, as indicated by the high allele frequency in East Asian populations and benign functional predictions. The missense variants were also recently reported in a cohort in eastern China, and the frequencies were similar between patients with PD and controls (17). Although the prevalence of c.297 + 21C > T was higher among our participants than among the enrolees of the Taiwan Biobank database, in silico pathogenicity predictors indicated that c.297 + 21C > T does not notably affect the mRNA splicing of UQCRC1. Allele frequencies more than 1% in East Asian populations are higher than expected for autosomal dominant disorders.

Recently, Senkevich et al. studied common and rare UQCRC1 variants according to GWAS and whole-genome sequencing data obtained from two large European cohorts (18). No common or rare variants in UQCRC1 were revealed to be associated with the risk of PD. Courtin et al. sampled 241 patients with FPD from 163 families with targeted or whole-exome sequencing; most of the patients were Europeans of European descent (19). They found no disease-causing variants of UQCRC1 among the study participants. Zhao et al. recruited 477 patients with FPD, 1,440 patients with sporadic EOPD, and 1,357 ethnicity-matched controls in their study; all participants were recruited from mainland China (20). In the study, a rare damaging variant (c.330G > C, p.E110D) was identified in one patient with sporadic EOPD, and one common synonymous variant (c.1419C > T, p.S473=) was revealed to be significantly associated with PD susceptibility. Furthermore, rs182453765 (p.S473=) was identified among four patients with EOPD in the present study. These results should be interpreted with caution and further validated with multiethnic cohorts.

The present study has a few limitations. First, only 107 patients with EOPD or FPD were involved. The sample size was insufficient for detecting significant genetic variants among the groups. Second, the onset ages of UQCRC1 heterozygotes carriers were reported to be 42–69 years by Lin et al. (4). Potential late-onset sporadic cases may have been excluded from our genetic study. Third, electrophysiologic data were not available for assessing polyneuropathy among the participants with UQCRC1 variants.

Overall, the results of this study indicate that the UQCRC1 gene may not be associated with EOPD or FPD among the Taiwanese population. Future studies with larger sample sizes and functional investigation are warranted to further understand the potential role of UQCRC1 in the onset of PD.

The data presented in the study are deposited in the Figshare repository, doi: 10.6084/m9.figshare.21525783.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Chang Gung Memorial Hospital (Ethical License No. 201701458B0C601). The patients/participants provided their written informed consent to participate in this study.

Y-RW: conceptualization, methodology, investigation, resources, writing—review and editing, supervision, project administration, and funding acquisition. T-WL: software and writing—original draft preparation. C-YC: validation, formal analysis, and visualization. T-WL and Y-RW: data curation. All authors have read and agreed to the published version of the manuscript.