During the past year we have published several studies identifying the extent and nature of LRRK2 mutation and variation. This work has been performed primarily in Parkinsons disease patients. Unlike most protocols we have taken a full screening approach, sequencing all 51 coding exons of LRRK2. In one of the cohorts used for this analysis, available from the NIH funded neurogenetics repository, we have also performed full sequence and gene dosage analysis of PARK2 and PARK6 loci. These data show a high level of PARK mutations and also demonstrate that mutations which are pathogenic when homozygous are present at a relatively high frequency (2%) as heterozygous changes in controls; this opposes a popular view that such heterozygous mutations act as risk loci for typical sporadic forms of Parkinson's disease.? We have continued assessment of PARK2, PARK6, PARK7, GCH1 and SNCA in Parkinson's disease cohorts, GCH1, PRKRA (identified by us) and TOR1A in dystonia cohorts and TTBK2, ITPR1 and SCA20 (all identified by us) in ataxia cohorts. This work has lead to the identification of several novel mutations.? We have, in addition, initiated a program of research in another synucleinopathy, multiple system atrophy, to examine brain tissue from subjects for this disease for somatic mutation at the synuclein locus, in addition to looking for the potential effects of synuclein SNPs as risk modifiers in this disease.? Our work on ALS has focussed on the examination of cases for mutations in SOD1, IFT74 and TDP43 and has resulted in the estimation of prevalence of such mutations and the identification of novel disease associated variants.
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