title: Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2.
abstract: The complex genetic etiology of Parkinson's disease (PD) is indicative of a multifactorial syndrome. A combination of gene-gene and gene-environment interactions may determine a variable phenotypic outcome. Recently a direct gene/protein interaction between two of the most common genetic causes of parkinsonism PRKN and LRRK2 has been postulated. We have identified three Spanish patients simultaneously harboring mutations in PRKN and LRRK2. In comparison to other Spanish patients with a single LRRK2 or PRKN mutation, the three double-mutation patients reported here do not present with an earlier age-at-onset or a faster progression of disease. Although the clinical findings do not support a synergistic effect of LRRK2 and PRKN, a potential genetic interplay might be concealed by the modulating effects of other genes. Nevertheless, this work demonstrates that the presence of mutations in one familial gene should not serve as exclusion criteria in a screen for further genetic variation. Direct interaction of Lrrk2 and parkin proteins was not observed in co-immunoprecipitation pull down experiments. However, in vivo studies are required to assess whether there is an indirect link between Lrrk2 and parkin in disease pathogenesis.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
authors.forename: Justus C
authors.initials: JC
authors.lastname: Dächsel
authors.forename: Ignacio F
authors.initials: IF
authors.lastname: Mata
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Julie P
authors.initials: JP
authors.lastname: Taylor
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Hinkle
authors.forename: Cecilia
authors.initials: C
authors.lastname: Huerta
authors.forename: Renee
authors.initials: R
authors.lastname: Ribacoba
authors.forename: Marta
authors.initials: M
authors.lastname: Blazquez
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013030:Spain; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases