Mutations in the gene encoding the ubiquitin E3 ligase Parkin gene have been identified
in autosomal recessively inherited forms of juvenile parkinsonism. Moreover single
amino acid substitutions in the Parkin protein were linked to the common sporadic
form of Parkinson disease (PD) acting as susceptibility alleles. We performed a mutation
screening in the Parkin gene in 25 index patients of German PD families with one or
more affected family members (mean age at disease onset 45.4±7.3 years). In two index
patients of families with apparent autosomal dominant inheritance of PD we identified
heterozygous point mutations encoding a novel P159L and a known R275W mutation, respectively.
No additional missense mutations or exon rearrangement were found in the index patients.
These mutations cosegregated with the disease in the respective families. Functional
analyses in HEK293 cells revealed an increased tendency to aggregate for P159L and
R275W mutant Parkin compared to wild type. These results indicate that aggregation-forming
capacity is not necessarily related to mutations in the RING finger domains of the
protein and support the role of heterozygous point mutations in the pathogenesis of
late onset PD. Our report provides genetic and functional evidence for 'dominantly
acting types' of Parkin mutations.
