Loss of Function Variants in LRKK1 and LRKK2 Not Linked to Parkinson Disease

Sheila Jacobs    September 21, 2018

Kinase inhibition or allele-specific targeting of mutant LRKK2 may still be a meaningful target for therapeutic development.

Research published in JAMA Neurologysuggests that haploinsufficiency of LRKK1or LRKK2 is not a cause of or protective against the development of Parkinson disease (PD), suggesting that kinase inhibition or allele-specific targeting of mutant LRKK2 may still be a meaningful target for therapeutic development in a subset of patients with PD.  

Next-generation sequencing data from a case-control cohort of >23,000 individuals were analyzed for loss of function (LOF) variants in LRKK1 and LRKK2, in order to establish the prevailing mechanism of LRRK-mediated disease. Data were generated at 5 different sites and 5 different datasets, which included both patients with clinically diagnosed PD (n=11,095) and neurologically normal controls (n=12,615). All data were gathered between 2012 and 2017. The main outcome measures was the frequency of LRKK1 and LRKK2 LOF variants in the general population, as well as a comparison of the frequency among cases vs controls. 

Of 11,095 patients with PD and 12,615 controls, LRRK1 LOF variants were identified in 0.205% vs 0.139%, respectively (odds ratio [OR] 1.48; 95% CI, 0.45-4.44; 

P =.49). In contrast, LRRK2 LOF variants were detected in 0.117% vs 0.087%, respectively (OR 1.48; 95% CI, 0.63-3.50; P =.36). Testing suggested a lack of association between LRKK1 or LRKK2 variants and PD. According to the findings, there was no significant enrichment in LRKK1 and LRKK2 LOF variants found in patients with PD (0.205% and 0.117%, respectively) compared with controls (0.139% vs 0.087%, respectively).

Additional analysis of lymphoblastoid cell lines from several LOF variant carriers demonstrated that, as anticipated, LRRK2 protein levels are decreased by approximately half compared with wild-type alleles.

The investigators concluded that the presence of LRKK1 and LRKK2 LOF variants does not increase an individual's risk for PD. The results of this analysis support the expansion of these studies in clinical trials and in cells from LRRK2 variant carriers.

Reference

Blauwendraat C, Reed X, Kia DA, et al; COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease) Consortium, the French Parkinson's Disease Consortium, and the International Parkinson's Disease Genomics Consortium (IPDGC). Frequency of loss of function variants in LRRK2 in Parkinson disease [published online July 23, 2018]. JAMA Neurol.

doi:10.1001/jamaneurol.2018.1885

https://www.neurologyadvisor.com/movement-disorders/parkinson-disease-risk-not-linked-to-lrkk1-lrkk2-variants/article/801373/