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Updated: Sep 18, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Loss-of-function coding variants in the Ras of complex proteins/GTPase domain of leucine rich repeat kinase 2
Sarah Butterfield1, Susanne Herbst1,2, Patrick Alfryn Lewis1,2
1Department of Comparative Biomedical Sciences, Royal Veterinary College, Camden Town, UK.
Abstract:
The LRRK2 gene is a key contributor to the genetic risk of Parkinson's disease, and a priority drug target for the disorder. Leucine Rich Repeat Kinase 2, the protein product of LRRK2, is a multidomain enzyme implicated in a range of cellular processes-including endolysosomal trafficking and damage response. Based on the report that truncation and structural variants resulting in loss of LRRK2 protein are observed in human populations, genomic sequence repositories were queried for coding variants affecting key catalytic residues in LRRK2-resulting in the identification of three variants (K1347E, K1347R, and T1348P) predicted to ablate the capacity of LRRK2 to bind GTP. Biochemical and cellular characterization of these variants confirmed loss of GTP binding, as well as reduced or loss of kinase activity. These data demonstrate the presence of rare coding enzymatic loss-of-function variants in humans, with implications for our understanding of LRRK2 as a driver of disease and as a drug target.
Insights
Rare genetic variants in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause loss of function, impacting Parkinson's disease risk. These findings are crucial for understanding LRRK2's role and developing new treatments.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a significant genetic risk factor for Parkinson's disease.
- LRRK2 protein plays a role in cellular processes like endolysosomal trafficking and damage response.
Purpose of the Study:
- To identify and characterize rare coding variants in LRRK2 that lead to loss of enzymatic function.
- To investigate the impact of these variants on GTP binding and kinase activity.
Main Methods:
- Genomic sequence repositories were queried for coding variants affecting key catalytic residues in LRRK2.
- Biochemical and cellular assays were used to characterize the identified variants (K1347E, K1347R, T1348P).
Main Results:
- Three novel LRRK2 variants (K1347E, K1347R, T1348P) were identified, predicted to abolish GTP binding.
- Experimental characterization confirmed the loss of GTP binding and reduced or abolished kinase activity for these variants.
Conclusions:
- Rare, enzymatic loss-of-function variants in LRRK2 exist in human populations.
- These findings have implications for understanding LRRK2's role in Parkinson's disease pathogenesis and its potential as a drug target.
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