LRRK1 and Parkinson's Disease

Multiple independent studies have evaluated the role of rare variants in LRRK1 (HGNC:18608) in Parkinson's disease (MONDO:0005180). An exome sequencing study in a family with late‑onset PD identified 15 potential variants and highlighted LRRK1 as a candidate based on segregation analysis in two affected individuals (PMID:24241507). In a separate multi‑patient study of 95 probands from families with autosomal dominant PD, 23 variants were identified in LRRK1, including 14 novel variants; however, the four non‑synonymous substitutions did not clearly segregate with disease and were not statistically overrepresented in PD cohorts (PMID:17225181). Additionally, a study in the Norwegian population reported four novel non‑synonymous coding variants in LRRK1 with no robust evidence of pathogenic segregation (PMID:17324517).

Functional assessments thus far have not demonstrated significant alterations in LRRK1 protein expression, localization, or activity. Comparative studies with its paralog LRRK2 indicate that LRRK1 is highly conserved, and its variants have not been shown to disrupt key cellular processes in Parkinson’s disease models. Overall, while rare LRRK1 variants have been recurrently detected in PD cohorts, lack of convincing segregation evidence and minimal functional disruption limit the current clinical validity of LRRK1 as a causative gene.

Key take‑home: Current evidence suggests that LRRK1 should be interpreted with caution in the molecular diagnosis of Parkinson’s disease pending further robust genetic and functional validation.

References

• Neurogenetics • 2014 • Rare variants in LRRK1 and Parkinson's disease PMID:24241507
• Neurogenetics • 2007 • Leucine‑rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease PMID:17225181
• Neuroscience Letters • 2007 • Variants in the LRRK1 gene and susceptibility to Parkinson's disease in Norway PMID:17324517

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