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

Lewthwaite, Alistair John (2009)
Ph.D. thesis, University of Birmingham.

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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.

Type of Work:Ph.D. thesis.
Supervisor(s):Morrison, Karen E. and Nicholl, David
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Medicine, Department of Clinical Neuroscience
Keywords:Parkinson's Disease, genetics, LRRK2, Dopa-responsive dystonia, GCH1
Subjects:QH426 Genetics
RC Internal medicine
Institution:University of Birmingham
ID Code:576
This unpublished thesis/dissertation is copyright of the author and/or third parties.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.
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