Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36

The cause of Parkinson disease (PD) is still unknown, but genetic factors h ave recently been implicated in the etiology of the disease. So far, four l oci responsible for autosomal dominant PD have been identified. Autosomal r ecessive juvenile parkinsonism (ARJP) is a clinically and genetically disti nct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been iden tified, and multiple mutations have been detected both in families with aut osomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD . In greater than or equal to 50% of families with ARJP that have been anal yzed, no mutations could be detected in the Parkin gene. We identified a la rge Sicilian family with four definitely affected members (the Marsala kind red). The phenotype was characterized by early-onset (range 32-48 years) pa rkinsonism, with slow progression and sustained response to levodopa. Linka ge of the disease to the Parkin gene was excluded. A genomewide homozygosit y screen was performed in the family. Linkage analysis and haplotype constr uction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1 . This region contains a novel locus for autosomal recessive early-onset pa rkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 w as obtained for marker D1S199.