Vaughan, Jenny Rosemary; (2001) Genetic susceptibility in Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Until 4 years ago, the role of genetic factors in the aetiology of PD was controversial but subsequently, a number of families have been identified, in whom parkinsonism is inherited as an apparently monogenic mendelian trait with high penetrance and in several of these families, disease genes have been identified. However, most cases of PD appear to be sporadic, with no clear mendelian mode of inheritance. The formation of the Genetic Susceptibility in Parkinson's disease (GSPD) enabled the clinical assessment, collection and analysis of DNA samples from a large number of affected sibling pairs (ASPs). Since 1996, three autosomal dominant PD loci have been described (PARK1, 3 AND 4), an average of 125 ASPs were therefore genotyped for evidence of linkage to these regions. For three markers D4S1647 (PARK1, alpha-synuclein, SNCA), D4S405 (Ubiquitin-C-terminal hydrolase, UCH-L1) and D2S1394 (PARK3, locus at 2pl3), nominal p-values of 0.05 or lower were observed suggesting the presence of susceptibility regions. A PARK4 (locus 4pl5) haplotype segregating with Parkinson's disease and postural tremor was detected in an Italian family. A large intra-familial association study using ASPs obtained by GSPD found that the slow acetylator genotype for N-acetyltransferase 2 (NAT2) was over-represented in familial PD. GSPD collaborative analysis of the SNCA and UCH-L1 gene failed to detect mutations by direct sequencing of SNCA and UCH-L1 in index cases from a series of PD kindreds or screening of 230 index familial PD cases for the two known mutations in SNCA. Hence, although of great interest, mutations in these genes are a very rare cause of familial PD, In contrast, analysis of the Parkin gene in selected families, sporadic and juvenile-onset cases showed that coding mutations in Parkin are a common cause of autosomal recessive parkinsonism in Europe. The neuropathology of the first UK case with a mutation in the Parkin is described. Two large familial PD kindreds in the UK were identified. No mutations were found in the SNCA gene and linkage studies to the other dominant familial PD loci were also negative. Further linkage and PET studies are ongoing to identify a novel familial PD locus in these individuals.

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