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Leucine-rich repeat kinase 2 is encoded by the LRRK2 gene and is causally linked to autosomal dominant Parkinson disease 8. Inheritance is autosomal dominant, with carriers developing late-onset parkinsonism characterized by bradykinesia, rigidity and resting tremor. The c.6059T>C (p.Ile2020Thr) variant was identified in a familial PARK8 patient and used to generate gene-corrected iPSCs that recapitulate key cellular phenotypes of PD in vitro (PMID:33181472).
Large-scale sequencing of 100 familial PD probands identified 26 LRRK2 coding variants; seven (including R1441C/G/H alleles) segregate with disease in multiple multiplex families and are absent from controls (PMID:16172858). Screening of 470 sporadic PD patients revealed two additional likely pathogenic variants (p.Arg1067Gln and IVS33+6T>A) in five cases (PMID:16247070). The hotspot p.Gly2019Ser variant occurs in 4/284 Swedish PD cases and 1/305 elderly controls, indicating incomplete penetrance (PMID:16817197). The p.Gly2385Arg allele is a common risk factor in Chinese cohorts, conferring ~2-fold increased PD susceptibility in 608 cases vs 373 controls (PMID:17160203).
The mutational spectrum comprises primarily missense substitutions clustering in the Roc/COR (e.g. p.Arg1441Cys, p.Arg1441Gly, p.Ile2020Thr) and kinase domains (e.g. p.Gly2019Ser), with additional variants in LRR and WD40 regions (e.g. p.Arg1067Gln, p.Leu119Pro). No loss-of-function truncating or deep-intronic variants have been reported. The p.Gly2385Arg allele shows a founder effect in East Asian populations.
Segregation analysis confirms co-segregation of pathogenic variants in at least seven multigenerational families, with a minimum of four additional affected relatives per kindred demonstrating autosomal dominant inheritance (PMID:16172858).
Functional studies support a gain-of-function mechanism. The p.Ile2020Thr mutant exhibits ~40% increased autophosphorylation versus wild-type in vitro (PMID:16321986), whereas p.Gly2019Ser and R1441 mutations enhance kinase activity and impair GTP hydrolysis, respectively (PMID:17584768; PMID:17442267). Mutant LRRK2 aberrantly associates with lipid rafts and disrupts synaptic vesicle endocytosis, linking kinase hyperactivity to neuronal dysfunction (PMID:17341485; PMID:18445495).
In vivo models recapitulate PD features: transgenic Drosophila expressing LRRK2-G2019S develop adult-onset dopaminergic neuron loss and locomotor impairment responsive to l-DOPA, confirming pathogenicity in vivo (PMID:18258746). Conversely, gene-corrected patient iPSCs reverse PD-related phenotypes, validating target specificity and therapeutic potential (PMID:33181472).
Integration: The convergence of genetic, segregation, and functional data fulfills ClinGen criteria for a Strong gene–disease association between LRRK2 and autosomal dominant Parkinson disease 8. Ongoing large-cohort studies and mechanistic dissection will refine penetrance estimates and guide biomarker development. Key take-home: LRRK2 mutation screening is clinically actionable for diagnosis, genetic counseling and selection of patients for targeted kinase-inhibitor trials.
Gene–Disease AssociationStrongAssociation supported by >100 familial and sporadic probands, segregation in multiple multigenerational families, and concordant functional data Genetic EvidenceStrong26 coding variants in 100 familial probands with seven segregating in multigenerational families; additional variants in >500 sporadic cases Functional EvidenceModerateMultiple in vitro kinase and GTPase assays, cellular and Drosophila models demonstrate gain-of-function and phenotypic rescue |