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

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.

Name dc:type.qualificationname

d_ph

Level dc:type.qualificationlevel

d_ph

Grantor dc:publisher.institution

University of Birmingham

Year dc:date.issued

2009

Author dc:creator

• Lewthwaite, Alistair John

• QH426 Genetics
• RC Internal medicine