Lewy bodies and parkinsonism in families with parkin mutations

Previous work has established that compound mutations and homozygous loss o f function of the parkin gene cause early-onset, autosomal recessive parkin sonism. Classically, this disease has been associated with loss of dopamine rgic neurons in the substantia nigra pars compacta and locus ceruleus, with out Lewy body pathology. We have sequenced the parkin gene of 38 patients w ith early-onset Parkinson's disease (< 41 years). Two probands with mutatio ns were followed up. Clinical evaluation of their families was performed, b linded to both genetic and pathological findings. Chromosome 6q25.2-27 hapl otype analysis was carried out independently of the trait, parkin gene expr ession was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kin dred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate t ranscripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of Parki n protein may lead to early onset parkinsonism with Lewy body pathology, wh ile a hemizygous mutation may confer increased susceptibility to typical Pa rkinson's disease.