Objective: This work aims to investigate the role of regulatory regions in Parkinson’s disease (PD) genes, which may help explain part of the missing heritability.

Background: Genetic diagnosis of  PD focuses primarily on coding genome regions, with limited results. While special emphasis has been placed on coding regions due to their important impact on protein function, many non-coding regions linked to this disease have emerged in GWAS (1,2). In addition, some associations of variants in the 3’UTR region of the SNCA gene have been described in PD (3). In this work, we explored 77 regulatory regions of 39 genes associated with PD in a series of 103 patients with early-onset Parkinson’s disease (EOPD).

Method: We used a custom panel that included regulatory regions chosen from ENCODE data. The first-level filtering criteria were MAF < 0.01 and a CADD score > 10. In silico analysis was conducted using JASPAR. The effect of variants on gene expression was examined through luciferase assays of genomic fragments containing the variants in cell lines. Functional genomics was performed on the patient’s fibroblasts.

Results: The non-coding variants prioritized after filtering the panel results were: PRKN:c.171+415T>C (intron 2/11), SNCA:c.-26+62G>T (intron 1/5), SNCA:c.*77C>A (3’-UTR), VPS35:c.*422C>A (3’-UTR), and DNAJC13:c.-253C>T (5’-UTR). Among them, the c.-253C>T variant of DNAJC13 (NM_015268.3) stood out with a CADD score of 18.22 and is classified as of uncertain significance (VUS, ACMG). In silico and functional studies showed that this variant affects gene regulation. The c.-253C>T variant is predicted to bind three new transcription factors compared to wild-type. WES analysis of the patient carrying this variant revealed no additional findings. Functional studies of promoter activity in cell lines indicated that c.-253C>T significantly impacted expression (Figure). In contrast, the patient’s fibroblasts exhibited a significant decrease in DNAJC13 expression under both normal (p=0.00066) and starvation conditions (p=0.0224). Furthermore, autophagy marker studies revealed defects in basal autophagy in the patient’s fibroblasts.

Conclusion: The association between DNAJC13 and PD has been controversial recently. However, the non-coding variant c.-253C>T in this gene represents a promising discovery, highlighting the significance of gene regulatory regions in the vulnerability of PD.

Figure

References: 1. DOI: 10.1016/S1474-4422(19)30320-5
2. DOI: 10.1093/brain/awac022
3. https://doi.org/10.1038/ncomms2032

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-regulatory-variant-c-253ct-of-the-dnajc13-gene-as-a-causal-factor-for-parkinsons-disease-in-a-patient-with-early-onset/