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 affecte d by autosomal-dominant probable Parkinson's disease. These regions have be en linked or associated with familial Parkinson's disease. Multipoint linka ge and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine fa milies. For three families, which were equivocal for two-point linkage at D 4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-LI) was sequenced . In one family, a novel UCH-LI M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in thi s gene may not be pathogenic. In seven of nine families, it could be inferr ed that affected individuals did not share 4q21-23 (alpha -synuclein) haplo types. 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 fi ve remaining families. Findings from this study confirm genetic heterogenei ty within familial parkinsonism.