LRRK2 – Parkinson disease

LRRK2 encodes a large, multidomain kinase linked to late-onset, autosomal dominant Parkinson disease. Affected individuals present with a tremor-predominant parkinsonism, bradykinesia, rigidity, and a robust levodopa response. Penetrance is age-dependent, rising from approximately 17% by age 50 to 85% by age 70.

Genetic studies have identified pathogenic LRRK2 missense variants co-segregating with parkinsonism in multiple families. The G2019S substitution was detected in 13 unrelated probands across Europe and North America, segregating with disease in 22 affected relatives (PMID:15726496). Haplotype analyses indicate a common founder and incomplete but age-related penetrance.

Independent case reports corroborate G2019S pathogenicity: three siblings and one sporadic patient from Ireland (PMID:16102999), and a Southern Italian family with maternal transmission (PMID:18621566). Additional missense variants—p.Arg1441Gly, p.Tyr1699Cys, p.Asn1437His, and p.Arg793Met—have been reported in familial and sporadic cases, demonstrating allelic heterogeneity.

The variant spectrum in PD comprises over 80 LRRK2 missense changes. G2019S remains the most frequent, accounting for ~2–6% of familial and 1–2% of sporadic PD. Recurrent founder mutations at codon 1441 (R1441G/C/H) explain regional clustering, while risk variants such as p.Gly2385Arg and p.Arg1628Pro modify susceptibility in Asian populations.

Functional assays demonstrate that PD-associated LRRK2 mutations enhance kinase activity and impair GTPase function, driving neuronal toxicity. In Caenorhabditis elegans, G2019S and R1441C variants increase vulnerability to mitochondrial toxins (PMID:19625511). Transgenic mice expressing G2019S LRRK2 exhibit progressive substantia nigra dopaminergic neuron loss via MKK4-JNK pathway activation (PMID:22539006).

Collectively, robust genetic segregation, a broad pathogenic variant spectrum, and concordant functional data establish a definitive association of LRRK2 with Parkinson disease. Routine LRRK2 testing informs diagnosis, familial risk assessment, and enrollment in targeted therapeutic trials.

Key Take-home: LRRK2 mutation screening is clinically essential for diagnosing autosomal dominant Parkinson disease and guiding precision medicine strategies.

References

• American Journal of Human Genetics • 2005 • Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. PMID:15726496
• Parkinsonism & related disorders • 2005 • Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD. PMID:16102999
• Parkinsonism & related disorders • 2009 • Genetic screening for LRRK2 gene G2019S mutation in Parkinson's disease patients from Southern Italy. PMID:18621566
• The Journal of Neuroscience • 2009 • LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. PMID:19625511
• Cell Death and Differentiation • 2012 • (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. PMID:22539006
• Journal of Medical Genetics • 2005 • The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. PMID:16272257

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