Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25.2-27 and identification of markers exhibiting linkage disequilibrium

Autosomal recessive juvenile parkinsonism (AR-JP) (MIM 600116) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with a mean age at onset of 23.2 years. We recently mapped the AR-JP gene locus to a 17-cM interval on chromosome 6q25.2-27. To further narrow the candidate region of the AR-JP gene, we performed detailed linkage analysis using densely placed genetic markers in this region (D6S437, D6S1581, D6S1579, D6S305, D6S411, SOD2, D6S253, D6S1599, D6S1719 and D6S264). Pairwise linkage analysis revealed the highest cumulative maximal lod score of 9.13 at D6S1579 (theta = 0.05), and multipoint linkage analysis revealed the highest cumulative lod score of 12.4 at the locus 3 cM telomeric to D6S1599. Observation of obligate recombination events narrowed the candidate region to a 13-cM region between D6S1579 and D6S264. Furthermore, we identified two marker loci, D6S1579 and D6S1599, which exhibit strong linkage disequilibrium with the AR-JP locus: chi(2) (2 x n table) = 84.22; P < 0.0001, chi(2) [likelihood-ratio test (LRT)] = 20.66; P < 0.0001, lambda = 0.40 and chi(2) (2 x n table) = 63.37; P < 0.0001, chi(2) (LRT) = 10.32; P < 0.0001, lambda = 0.30, respectively. These results suggest that the candidate region for the AR-JP gene is most likely located near the 4-cM region encompassing D6S1579 and D6S1599.