TY - JOUR
T1 - The PARK8 Locus in Autosomal Dominant Parkinsonism
T2 - Confirmation of Linkage and Further Delineation of the Disease-Containing Interval
AU - Zimprich, Alexander
AU - Müller-Myhsok, Bertram
AU - Farrer, Matthew
AU - Leitner, Petra
AU - Sharma, Manu
AU - Hulihan, Mary
AU - Lockhart, Paul
AU - Strongosky, Audrey
AU - Kachergus, Jennifer
AU - Calne, Donald B.
AU - Stoessl, Jon
AU - Uitti, Ryan J.
AU - Pfeiffer, Ronald F.
AU - Trenkwalder, Claudia
AU - Homann, Nikolaus
AU - Ott, Erwin
AU - Wenzel, Karoline
AU - Asmus, Friedrich
AU - Hardy, John
AU - Wszolek, Zbigniew
AU - Gasser, Thomas
N1 - Funding Information:
We thank all family members who participated in our study. This work was supported by National Institutes of Health Udall Grant NS40256 and by a grant from the Bundesministerium für Bildung und Forschung (Nationales Genomforschungsnetz, NV S15T02). T.G. was also supported by Deutsche Forschungsgemeinschaft grant Ga 402/10-1. P.L. is the recipient of a Smith fellowship.
PY - 2004/1
Y1 - 2004/1
N2 - 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.
AB - 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.
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U2 - 10.1086/380647
DO - 10.1086/380647
M3 - Article
C2 - 14691730
AN - SCOPUS:9144261126
SN - 0002-9297
VL - 74
SP - 11
EP - 19
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -