A susceptibility locus for Parkinson's disease maps to chromosome 2p13

Abstract

Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas¹. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease². Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects³ and questioned earlier studies which had denied such influences⁴. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically⁵ and in some cases also neuropathologically^6,7. Recently, a disease locus has been mapped to chromosome 4q21–22 in a large Mediterranean pedigree⁸, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death⁹. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding α-synuclein¹⁰. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkin-sonism was not linked to the 4q-locus¹¹ and was not associated with the α-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.