Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the Parkin gene in affected individuals

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical an d genetic entity characterized by selective degeneration of nigral dopamine rgic neurons and young-onset parkinsonism with remarkable response to levod opa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consistin g of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecul ar analysis on 34 affected individuals from 18 unrelated families with AR-J P. We found four different homozygous intragenic deletional mutations, invo lving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel on e-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic dele tion accounted for 50% (17 of 34) and the one-base deletion accounted for 6 % (2/34); in the remaining, no homozygous mutations mere found in the codin g regions. Our findings indicate that loss of function of the Parkin protei n results in the clinical phenotype of AR-JP and that subregions between in trons 2 and 5 of the Parkin gene are mutational hot spots.