title: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
abstract: We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
authors.affiliation: Department of Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Petra
authors.initials: P
authors.lastname: Leitner
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Matthew
authors.initials: M
authors.lastname: Farrer
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kachergus
authors.forename: Mary
authors.initials: M
authors.lastname: Hulihan
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Pfeiffer
authors.forename: Nadja
authors.initials: N
authors.lastname: Patenge
authors.forename: Iria Carballo
authors.initials: IC
authors.lastname: Carbajal
authors.forename: Peter
authors.initials: P
authors.lastname: Vieregge
authors.forename: Friedrich
authors.initials: F
authors.lastname: Asmus
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D001921:Brain / Q000473:pathology*; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D011494:Protein Kinases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases