title: Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease.
abstract: Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.
authors.affiliation: Department of Neurology, St. Olav's Hospital, Trondheim, Norway.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
authors.forename: Justus C
authors.initials: JC
authors.lastname: Dachsel
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Webber
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Haugarvoll
authors.forename: Krisztina K
authors.initials: KK
authors.lastname: Johansen
authors.forename: Mathias
authors.initials: M
authors.lastname: Toft
authors.forename: John G
authors.initials: JG
authors.lastname: Nutt
authors.forename: Haydeh
authors.initials: H
authors.lastname: Payami
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kachergus
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Amela
authors.initials: A
authors.lastname: Felic
authors.forename: Christian
authors.initials: C
authors.lastname: Wider
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cobb
authors.forename: Linda R
authors.initials: LR
authors.lastname: White
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001216:Asparagine / Q000235:genetics*; D002461:Cell Line, Transformed; D005260:Female; D005820:Genetic Testing; D006160:Guanosine Triphosphate / Q000378:metabolism; D006639:Histidine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009664:Norway; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D006639:Histidine; D001216:Asparagine; D006160:Guanosine Triphosphate; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases