Linkage exclusion in French families with probable Parkinson' s disease.

We analyzed the segregation of genetic markers spanning chromosomal regions 2p13, 4p14-15, 4q21-23, 6q25-27, and 17q21 in nine French families affected by autosomal-dominant probable Parkinson's disease. These regions have been linked or associated with familial Parkinson's disease. Multipoint linkage and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine families. For three families, which were equivocal for two-point linkage at D4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-L1) was sequenced. In one family, a novel UCH-L1 M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in this gene may not be pathogenic. In seven of nine families, it could be inferred that affected individuals did not share 4q21-23 (alpha-synuclein) haplotypes. All families were unequivocally excluded by haplotype analysis from the parkin locus on 6q25-27. Finally, the 17q21 region was excluded in four of nine families, and no mutation in the tau gene was identified in the five remaining families. Findings from this study confirm genetic heterogeneity within familial parkinsonism.