Localization of a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, PARK6, on Human Chromosome 1p35-p36

Abstract

The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct 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 identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction 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 parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…The clinical picture was similar to typical PD apart from early onset and slow progression with sustained response to levodopa [230]. No neuropathological data were available.…”

Autophagy and human diseases

“…Many genes, mutations, and polymorphisms have been implicated in the pathogenesis of the disease. Among them, mutations in the PARK2/Parkin and PARK6/PINK1 have been shown to lead to autosomal recessive or sporadic juvenile-onset Parkinson's disease [52][53][54].…”

Biomarkers of neurodegenerative disorders: How good are they?

“…G309D was found in a Spanish family and W437OPA substitutions were found in two Italian families [39]. Studies show that PINK1 mutations are associated with PARK6, a locus relating with autosomal recessive, early-onset PD on chromosome 1p35-p36 by autozygosity mapping in a large consanguineous family from Sicily [51]. Subsequent identification of two additional consanguineous families provided additional evidence of the relationship with PARK6 [52].…”