title: Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration.
abstract: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.
  
  
  
  To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.
  
  
  
  LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.
  
  
  
  Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Monica
authors.identifier: 0000-0002-3092-2781
authors.initials: M
authors.lastname: Sanchez-Contreras
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Tacik
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Diehl
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Christopher
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Walton
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D001480:Basal Ganglia Diseases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D013494:Supranuclear Palsy, Progressive / Q000097:blood / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: CBD; LRRK2; PSP; mutation; tauopathy