Objective: In this study, we investigate the Hypothesis 1 using Next-generation sequencing (NGS).

Background: In 1998, we reported homozygous mutations of PRKN as the causative gene of juvenile Parkinson’s disease (PD). Furthermore, we identified PD patients with heterozygous PRKN mutations whose ages at onset were relatively early (40.6±16.2y, n=66), although the mechanism of the onset is not elucidated. We propose two hypotheses: (Hypothesis 1) There are additional variants in the intronic region of PRKN, which are involved in the onset of PD with heterozygous PRKN mutations and (Hypothesis 2) Disease modifier genes (genes other than PRKN) are associated with the onset of PD with heterozygous PRKN mutations.

Method: We used targeted sequencing and sequenced 1,453,246bp including the 5’UTR and 3′ UTR of PRKN. Targeted sequencing was performed by 1,624,271 bp paired-end sequencing on HiSeq2500 (Illumina,CA). Sample preparation for targeted sequencing was performed using SureSelect QXT Library Prep Kit (Agilent Technologies, CA) and SeqCap EZ Prime Choice system (Roche Diagnostics, IN).

Results: We enrolled 3 groups (total 288 subjects): (i) PD with heterozygous PRKN mutations (n=51), (ii) PD with homozygous mutations whose parents are not PD (n=105) and (iii) healthy controls (n=132). Analysis of NGS is under the investigation.

Conclusion: If Hypothesis 1 could be proved, it would be possible to diagnose many patients who were previously judged as negative by genetic tests. Furthermore, analyses of the intronic region of the PRKN gene might be necessary for the future genetic diagnosis, and a paradigm shift would be led. If Hypothesis 2 could be proved, it would be possible to shed new light on the new pathway associated PRKN mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detection-of-genetic-modifiers-in-prkn/