title: The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval.
abstract: Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.
authors.affiliation: Hertie-Institute for Clinical Brain Research, Department for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Matthew
authors.initials: M
authors.lastname: Farrer
authors.forename: Petra
authors.initials: P
authors.lastname: Leitner
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Mary
authors.initials: M
authors.lastname: Hulihan
authors.forename: Paul
authors.initials: P
authors.lastname: Lockhart
authors.forename: Audrey
authors.initials: A
authors.lastname: Strongosky
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kachergus
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: Jon
authors.initials: J
authors.lastname: Stoessl
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Pfeiffer
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Homann
authors.forename: Erwin
authors.initials: E
authors.lastname: Ott
authors.forename: Karoline
authors.initials: K
authors.lastname: Wenzel
authors.forename: Friedrich
authors.initials: F
authors.lastname: Asmus
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wszolek
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
mesh_terms: D002874:Chromosome Mapping; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D014055:Tomography, Emission-Computed; D044465:White People