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

Abstract

Autosomal recessive juvenile parkinsonism (AR‐JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young‐onset parkinsonism with remarkable response to levodopa. 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, consisting 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 molecular analysis on 34 affected individuals from 18 unrelated families with AR‐JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exo 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one‐base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one‐base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR‐JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.