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Identification of genetic modifiers in LRRK2 parkinsonism

University of British Columbia

Genetic studies have been extremely informative to the pathophysiology of PD. The most common pathogenic mutation discovered is LRRK2 p.G2019S which accounts for 30-40% of Parkinson disease (PD) in North African Arab Berbers, 18-30% in Ashkenazi Jews and 1-3% in Caucasians. Although LRRK2 p.G2019S parkinsonism is considered a monogenic form of disease, disease penetrance of motor symptoms is variable. We hypothesize that genetic factors can modulate the phenoconversion of LRRK2 p.G2019S which could lead to treatments that prevent onset or delay disease progression. Clinical characterization of LRRK2 p.G2019S carriers from Tunisia was performed by analysis of motor and non-motor features. Genetic analysis of age of onset as a genetic trait was performed in a cohort of Tunisian Arab Berbers with LRRK2 p.G2019S. Short-tandem repeat genotyping (4cM resolution) and non-parametric and model-based genome-wide linkage was evaluated in 41 multi-incident LRRK2 p.G2019S families. High-density locus-specific genotyping and association analyses were also performed in 232 unrelated LRRK2 p.G2019S carriers. Genome sequencing in a subset of 25 subjects informed imputation and haplotype analyses. Validation analysis used Sanger sequencing and Taqman genotyping on additional LRRK2 p.G2019S carriers originating from Algeria, France and Norway. Whole transcriptome, candidate gene and protein expression was assessed in striatum from 60 human brains. Significant linkage was identified on chromosome 1q23.3-24.3 (model-based LOD=4.99, D1S2768). In the chromosome 1q23.3-24. interval higher-resolution SNP genotyping, association and haplotype mapping nominated genetic variability within DNM3 as an age of onset modifier of disease penetrance (rs2421947 nominal p<10-⁵; haplotype p=1.67 x 10-⁷). In terms of age of onset the penetrance of parkinsonism in LRRK2 p.G2019S carriers varies as a function of DNM3 genotype; rs2421947 is a haplotype-tag for which median onset in GG carriers is 13 years younger than CC carriers (HR 1.63 CI=1.05-2.63, p=0.03). DNM3 rs2421947 variability is also directly correlated with dynamin 3 mRNA and protein expression in human brain striatum (p<0.05). Dynamin 3, shown to complex with endophilin A, LRRK2 and vacuolar protein sorting 35, localizes to the endocytic machinery of dendritic spines to modulate receptor recycling and excitatory synaptic transmission, now suggests novel targets for therapeutic development in Parkinson’s disease.

Text

2017-01-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59991

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/