Genetic studies of candidate genes in Parkinson’s disease

Abstract

The genetics of Parkinson’s disease (PD) have been extensively studied during recent years. This thesis presents an investigation of genetic causes of Parkinson’s disease in differently structured population samples using a candidate gene approach. The main part (Paper I-IV; Results chapter 5.1 Part I) consist of association and genetic studies of candidate genes in idiopathic late-onset, early-onset and familial Parkinson’s disease mainly in a homogenous Norwegian population. The latter part (Paper V; Results chapter 5.2 Part II) is a genetic analyses of candidate genes in cases with young-onset and juvenile parkinsonism in consanguineous Jordanian families.

The aim of this research was to investigate candidate genes to examine if a genetic cause could be associated to or explain disease in some of the affected. In the Norwegian population, the case-control association studies of idiopathic PD focused on synphilin-1 and alpha-synuclein, two of the genes of which gene products are found in Lewy bodies a pathological hallmark of PD. As the alpha-synuclein gene was previously associated with PD through mutations in familial cases with autosomal dominant inheritance and later in several families with whole gene dosage mutations increasing copy number, we addressed the different genetic aspects of alpha-synuclein in relevant sample populations. A possible involvement of PINK1 was also investigated in a relevant Norwegian sample population. The affected in the Jordanian sample population were from consanguineous families from a region with a high degree of consanguinity. The affected had been diagnosed with youngonset parkinsonism with an autosomal recessive inheritance pattern inferred although some affected strictly were young-onset sporadic incidences. Genetic analysis of the parkin and PINK1 gene was performed on the basis that mutations in these two genes were known to be the cause of autosomal recessively inherited parkinsonism in an increasing number of similar cases.

The methodological approach varied depending on clinical structure and pattern of inheritance observed in the sample population in question. In the Norwegian population of late-onset idiopathic PD we used a direct and indirect approach with haplotype analysis, to test for candidate gene association for synphilin-1and alpha-synuclein. A genetic analysis approach was applied in the study of the Jordanian population which consisted of affected with young on set parkinsonism in consanguineous families. The main approaches to analyse the various sample populations complement each other among the wide range of methods available for genetic level analyses.

In the Norwegian population the tested genetic variation insynphilin-1 was not associated with development of PD and we could not confirm a previously reported putative pathogenic R621C mutation in the gene. In alpha-synuclein a haplotype that encompassed the gene suggested a common genetic cause of idiopathic PD in the Norwegian population and coupled a previous 5’ promoter association with a more recently identified 3’ in the same associated haplotype.

In a collection of probands of families with autosomal dominant parkinsonism, we concluded that the observed pattern of inheritance was not due to gene mutations in the alpha-synuclein gene or whole locus multiplications. In Norwegian cases of early-onset or late-onset familial PD a few cases were observed with heterozygous PINK1 gene mutations (G411S, P498L) adding to the debate on the role of carrying heterozygous mutations and the development of PD.

The Jordanian parkin gene analysis identified a three generation family with an exon 4 deletion within a haplotype that segregated with disease. Both affected in the family were homozygous for the deletion. In the Jordanian PINK1 gene study two putative novel pathogenic mutations were identified. One of the putative pathogenic mutations (P416R) was located in a highly conserved motif of the PINK1 gene, another putative pathogenic mutation(S419P) was located in a conserved region of the gene, both present in homozygous state in two affected in their respective families. A PINK1 gene Q34R substitution identified in the population sample is also found in India suggesting some shared genetic ancestry. The Jordanian studies are a contribution to genetic knowledge on young-onset parkinsonism in a geographic region less well studied than the European and in a population with a high degree of consanguinity.