A clinical and molecular genetic study into familial and sporadic Parkinson’s Disease

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http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/1393 http://eprints.org/relation/ispreviewThumbnailVersionOf http://etheses.bham.ac.uk/id/document/1393 http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/1393 archive 4031 disk0/00/00/05/76 2010-03-17 10:08:27 2019-01-23 09:52:25 2011-07-19 16:19:43 thesis show 0 Lewthwaite Alistair John Alistair.Lewthwaite@uhb.nhs.uk Morrison Karen E. Nicholl David University of Birmingham A clinical and molecular genetic study into familial and sporadic Parkinson’s Disease unpub QH426 RC 10col_mede Parkinson's Disease, genetics, LRRK2, Dopa-responsive dystonia, GCH1 Parkinson’s disease (PD) is a neurodegenerative disease which causes tremor, muscular rigidity and bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions). Although the underlying causes remain unknown, there is evidence that genetic factors play an important role in the disease process. In this thesis I investigated the role of a recently identified hereditary PD gene leucine rich repeat kinase 2 (LRRK2) in PD in the United Kingdom (UK). In this thesis I have confirmed the importance of pathogenic LRRK2 mutations in UK familial PD (fPD). In addition I identified three novel frameshift mutations. I investigated the functional effects of two of these mutations and provide evidence that nonsense mediated decay (NMD) is occurring in LRRK2-PD. In this thesis I also present data from an extensive screen of LRRK2 in UK subjects with sporadic PD (sPD). This confirms the importance of pathogenic LRRK2 mutations in UK sPD. In addition I report a novel missense mutation in the GTP cyclohydrolase I gene (GCH1) in a kindred with phenotypes ranging from PD to Dopa-responsive dystonia. The association of this novel GCH1 mutation with late onset parkinsonism suggests a potential role for GCH1 in PD. 2009-12 2009-03 graduation eng author unchecked This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Parkinson's UK public 435 University of Birmingham School of Clinical and Experimental Medicine d_ph other 2009-12 graduation