Genotype-driven therapeutic developments in Parkinson’s disease

Prasuhn, Jannik; Brüggemann, Norbert

doi:10.1186/s10020-021-00281-8

Molecular Medicine

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

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
? 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
*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

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ISSN: 1528-3658

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