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 areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, 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 death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data).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.

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

“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

“…Linkage to chromosome 2p (PARK3) was reported in six families primarily of German-American and Danish-American origin with autosomal dominant PD in 1998 [169].…”

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

“…The PARK3 locus (MIM 602404) on chromosome 2p13 was initially reported to be associated with PD affection status in an autosomal dominant model of PD using 6 European families, each with at least 4 affected PD relatives (Gasser et al, 1998). PARK3 was later shown to be linked and associated with age of onset of PD in the GenePD Study using 103 multiplex families (DeStefano et al, 2002).…”

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

“…The products of these genes are alpha-synuclein (SNCA), parkin (ubiquitin-conjugating enzyme; UBCH7; PARK2), ubiquitin Cterminal hydrolase L1 (UCHL1), PTEN-induced kinase 1 (PINK), DJ-1 and leucine-rich repeat kinase 2 (LRRK2). Additional loci harbouring presumptive PD genes have been mapped including PARK3 [19], PARK10 [24] and PARK11 [51].…”