Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed

Cathepsin B p.Gly284Val variant in Parkinsons disease pathogenesis

Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk