Table 1 Genes implicated in Parkinson disease and atypical parkinsonian syndromes
Gene | MOI | Mutation spectrum | Mutation mechanism | Clinical phenotype | Levodopa response | Pathology | Protein product | Pathway | References |
|---|---|---|---|---|---|---|---|---|---|
ATP10B | AR | Missense and splice site mutations | LOF | EOPD/LOPD | Limited, levodopa-induced dyskinesia | Unknown | Phospholipid transporting ATPase 10B | Endo-lysosome | [213] |
ATP13A2 | AR | Missense and PTC mutations | LOF | Juvenile APS called Kufor-Rakeb syndrome with pyramidal signs, supranuclear gaze palsy and cognitive impairment; NCL; HSP | Good | Lipofuscinosis | Cation transporting ATPase 13A2 | Endo-lysosome | |
ATP6AP2 | XR | p.Ser115Ser and p.Asp107Asp | LOF | Juvenile APS with slow disease progression and considerable phenotypic variability including spasticity, intellectual disability and epilepsy | Limited, levodopa-induced dyskinesia | LB-, tau+b | Renin/prorenin receptor | Endo-lysosome | |
DJ-1 | AR | Deletions, PTC and missense mutations | LOF | EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment | Limited, levodopa-induced dyskinesia | LB + b | DJ-1 | Mitochondria | |
DNAJC6 | AR | c.802-2A > G, p.Thr741Thr, p.Gln791b, p.Gln846b, p.Arg927Gly | LOF | Juvenile and early-onset APS with rapidly disease progression and possible intellectual disability, seizures and pyramidal signs. | Limited, levodopa-induced dyskinesia and psychiatric features | Unknown | Auxilin | Vesicular transport | |
FBXO7 | AR | PTC and missense mutations | LOF | Ranging from classic EOPD to juvenile APS with pyramidal signs (spasticity, impaired fine movements and increased reflexes) | Limited, levodopa-induced dyskinesia and psychiatric features | Unknown | F-box protein 7 | Mitochondria | |
PARK2 | AR | Deletions, PTC and missense mutations | LOF | EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment | Limited, levodopa-induced dyskinesia | Most LB- | Parkin | Mitochondria | |
PINK1 | AR | Deletions, PTC and missense mutations | LOF | EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment | Limited, levodopa-induced dyskinesia | LB + b | PTEN-induced kinase 1 | Mitochondria | |
PLA2G6 | AR | CNV, PTC and missense mutations | LOF | Early-onset APS called dystonia-parkinsonism with cognitive decline, autonomic dysfunction and psychiatric manifestations; INAD; atypical NAD | Limited, levodopa-induced dyskinesia | Axonal spheroid, iron deposits | Phospholipase A2 | Endo-lysosome | |
LRRK2 | AD | Missense mutations | GOF | LOPD with slow disease progression and rarely cognitive impairment | Good | Most LB+, rarely tau+ | Leucine-rich repeat kinase 2 | Vesicular transport | |
SNCA | AD | Multiplications, p.Ala30Pro, p.Glu46Lys, p.Gly51Asp, p.Ala53Glu and p.Ala53Thra | GOF | EOPD/LOPD with severe, rapidly disease progression and cognitive impairment; DLB; MSA | Good | LB+ | α-Synuclein | Vesicular transport | |
SYNJ1 | AR | p.Arg258Gln, p.Arg459Pro | LOF | Juvenile APS with possible cognitive impairment, epilepsy and dystonia | Limited, levodopa-induced dyskinesia | LB-, tau+b | Synaptojanin 1 | Vesicular transport | |
VPS13C | AR | Deletions and PTC mutations | LOF | EOPD/DLB with severe, rapidly disease progression and cognitive decline | Good | LB+ | Vacuolar protein sorting 13C | Endo-lysosome | |
VPS35 | AD | p.Asp620Asn | LOF | LOPD with slow disease progression and rarely cognitive impairment or neuropsychiatric symptoms | Good | Unknown | Vacuolar protein sorting 35 | Vesicular transport |