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Table 1 Monogenic traits of Parkinson’s disease

From: Genotype-driven therapeutic developments in Parkinson’s disease

Gene name Mode of inheritance Frequency Mutation Proposed disease mechanisms Predominantly involved pathway(s) Predominant phenotype
SNCA AD Very rare Missense or multiplication GoF α-Synuclein aggregation Duplication: resembles PD
Missense/triplication: LBD-like
POLG AD Rare Missense LoF? Mitochondrial impairment Atypical PD with features of mitochondriopathy
VPS35 AD Very rare Missense
(up to 100%: D620N)
LoF Endosomal/lysosomal dysfunction Resembles PD
DNAJC13 AD Very rare Missense LoF? Co-chaperones and endosomal/lysosomal dysfunction Atypical PD
LRRK2 AD (incomplete penetrance) Population-dependent* Missense (76% G2019S**) GoF Endosomal/lysosomal dysfunction;
mitochondrial impairment
More beneficial disease course as PD
PRKN AR Rare Missense or deletions LoF Mitochondrial impairment EOPD
PINK1 AR Very rare Missense or deletions LoF Mitochondrial impairment EOPD
PARK7 AR Very rare Missense or deletions LoF Mitochondrial impairment EOPD
ATP13A2 AR Very rare Missense or deletions LoF Endosomal/lysosomal dysfunction? Atypical PD
Complex HSP
FBXO7 AR Very rare Missense LoF Mitochondrial impairment and endosomal/lysosomal dysfunction Often EOPD
PLA2G6 AR Very rare Missense or deletions LoF Phospholipid remodeling, arachidonic acid release, leukotriene and prostaglandin synthesis, and fas‐mediated apoptosis;
α-synuclein aggregation
often EOPD
DNAJC6 AR Very rare Missense or deletions LoF Endosomal/lysosomal dysfunction Atypical PD
SYNJ1 AR Very rare Missense or deletions LoF Endosomal/lysosomal dysfunction Atypical PD
VPS13C AR Very rare Missense or deletions LoF Mitochondrial impairment Resembles PD
GBA Genetic risk factor Common Missense or deletions*** LoF Endosomal/lysosomal dysfunction More aggressive disease course as PD
  1. The table shows independently confirmed PD genes, in which functional data is available to interpret the underlying pathomechanism. The frequency is listed as a relative measure and is based on the evaluation of the authors. The question marks depict the current level of uncertainty or unknown aspects of distinct genes
  2. ? unclear/uncertain, AD autosomal dominant, AR autosomal recessive, ATP13A2 ATPase Cation Transporting 13A2, PARK7 oncogene DJ-1, DNAJC13 DnaJ Heat Shock Protein Family (Hsp40) Member C13, DNAJC6 DnaJ Heat Shock Protein Family (Hsp40) Member C6, EOPD early-onset Parkinson’s disease, FBXO7 F-Box Protein 7, GBA Glucosylceramidase Beta, GoF gain of function, LoF loss of function, LRRK2 Leucine Rich Repeat Kinase 2, PD Parkinson’s disease, PINK1 PTEN-induced kinase 1, PLA2G6 Phospholipase A2 Group VI, POLG Mitochondrial Polymerase Gamma, PRKN Parkin, SNCA α-synuclein, SYNJ1 Synaptojanin 1, VPS13C Vacuolar Protein Sorting 13 Homolog C, VPS35 VPS35 Retromer Complex Component, HSP hereditary spastic paraplegia, LBD Lewy body dementia
  3. *Approx. 20% in Ashkenazi Jews and 40% in North African Berbers (Healy et al. 2008; Lesage et al. 2006), ~ 1% in white (European or North-American ancestry) population (Heckman et al. 2013). **based on MDSGene data (https://www.mdsgene.org/d/1/g/1?action=plot&fc=0&_mu=1&_country=1 date of access: 4th of February 2021). ***Severe/Pathogenic variant: previously described in Gaucher disease, Mild/Risk factor: associated with an increased risk of PD, but not causative for Gaucher disease