title: Genetic factors influencing age at onset in LRRK2-linked Parkinson disease.
abstract: Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families. Using this limited number of available LRRK2 mutation carriers, we provide evidence that mutations in the kinase domain of Lrrk2 significantly decrease AAO compared to mutations in the ROC (Ras/GTPase of complex proteins) domain. Furthermore, polymorphic variations in MAPT show a significant association with AAO in individuals with LRRK2 mutations. Our results await replication in future studies with a larger number of LRRK2 mutation carriers, but indicate an association of mutation-affected protein domain and mutation-extrinsic genetic factors with AAO and suggest that these factors could contribute to explain the phenotypic heterogeneity observed in LRRK2-linked PD.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Golub
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Pfeiffer
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Jakob C
authors.initials: JC
authors.lastname: Mueller
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Julia
authors.initials: J
authors.lastname: Fuchs
mesh_terms: D017668:Age of Onset; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases