LRRK2 (Leucine-Rich Repeat Kinase 2): Genetics, Function, and Clinical Significance
A comprehensive biomedical overview of LRRK2, a key gene in Parkinson's disease and potential therapeutic target.
Gene Information Card
| Symbol | LRRK2 |
|---|---|
| Full Name | Leucine-rich repeat kinase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 12q12 |
| NCBI Gene ID | 120892 ncbi.nlm.nih.gov/gene/120892 |
| Ensembl ID | ENSG00000188906 |
| UniProt ID | Q5S007 |
| OMIM ID | 609007 |
| HGNC ID | 18698 |
| Aliases | PARK8, DARDARIN, AURA17 |
Description
LRRK2 encodes a large multidomain protein kinase (dardarin) involved in various cellular processes, including vesicle trafficking, autophagy, and mitochondrial function. Mutations in LRRK2 are the most common genetic cause of familial and sporadic Parkinson's disease (PD), with the G2019S mutation being particularly prevalent. The protein contains both GTPase and kinase domains, making it a promising target for therapeutic intervention.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Parkinson's disease (autosomal dominant) | Gain-of-function mutations (e.g., G2019S) increase kinase activity, leading to neurotoxicity and dopaminergic neuron degeneration. | ClinVar, OMIM |
| Crohn's disease | Risk variants (e.g., M2397T) may alter immune cell function and autophagy, contributing to intestinal inflammation. | ClinVar, OMIM |
| Cancer (e.g., renal cell carcinoma, lung cancer) | Somatic mutations and altered expression may influence cell proliferation and survival pathways. | COSMIC, literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (substantia nigra) | ~10 | Moderate |
| Kidney | ~15 | Moderate |
| Lung | ~8 | Low |
| Liver | ~5 | Low |
| Spleen | ~7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | ~12 | Neuronal model |
| HEK293 (embryonic kidney) | ~18 | High expression |
| A549 (lung carcinoma) | ~9 | Moderate |
| HepG2 (hepatoma) | ~6 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| G2019S | Missense | ~1-2% of sporadic PD; ~4% of familial PD | Increased kinase activity, toxic gain-of-function |
| R1441C/G/H | Missense | Rare, familial PD | Reduced GTPase activity, altered signaling |
| Y1699C | Missense | Rare, familial PD | Impaired GTPase/kinase regulation |
| I2020T | Missense | Rare, familial PD | Increased kinase activity |
| M2397T | Missense | Risk factor for Crohn's disease | Altered immune function |
Mutation functional classification
Loss of Function (LOF)
Not well established; most pathogenic mutations are gain-of-function or dominant-negative.
Gain of Function (GOF)
G2019S and I2020T increase kinase activity, leading to neurotoxicity.
Dominant Negative (DN)
R1441C and Y1699C may act as dominant-negative by disrupting GTPase function and dimerization.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Endocytosis and vesicle trafficking
• Autophagy regulation
• Mitochondrial homeostasis
• Wnt signaling
• Inflammatory response
Protein Summary
LRRK2 is a 2527-amino acid protein with multiple domains: ankyrin repeat, leucine-rich repeat, GTPase (Roc), COR, kinase, and WD40 domains. It functions as a serine/threonine kinase and GTPase, regulating vesicle dynamics, autophagy, and mitochondrial function. Pathogenic mutations, particularly in the kinase and GTPase domains, disrupt these processes, leading to neurodegeneration. The protein is expressed in various tissues, with highest levels in the brain, kidney, and immune cells. Its kinase activity is a major therapeutic target for PD.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| LRRK2 Knockout HEK293 Cell Line | EDJ-KQ7015 | Human | 120892 | Details Get a Quote |
| LRRK2 Knockout A-549 Cell Line | EDJ-KQ33079 | Human | 120892 | Details Get a Quote |
| LRRK2 Knockout HeLa Cell Line | EDJ-KQ58071 | Human | 120892 | Details Get a Quote |
| LRRK2 Knockout HCT 116 Cell Line | EDJ-KQ74975 | Human | 120892 | Details Get a Quote |
| LRRK2（p.C2024A and p.C2025A） Point Mutation in A-549 Cell Line | EDC03252 | Human | 120892 | Details Get a Quote |
| LRRK2（p.C2024A） Point Mutation in A-549 Cell Line | EDC03246 | Human | 120892 | Details Get a Quote |
| LRRK2（p.C2025A） Point Mutation in A-549 Cell Line | EDC03254 | Human | 120892 | Details Get a Quote |
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