PLA2G6 – Autosomal Recessive Parkinson Disease 14

Autosomal recessive mutations in PLA2G6, encoding group VIA calcium-independent phospholipase A2, underlie PARK14, an early-onset, L-DOPA-responsive dystonia-parkinsonism (MONDO:0013060). Affected individuals present with bradykinesia, tremor, and cognitive decline, often with iron accumulation or cerebellar atrophy on imaging.

Initial clinical evidence emerged from a consanguineous Turkish family: a 33-year-old index with early-onset parkinsonism harbored homozygous c.2239C>T (p.Arg747Trp), which segregated with disease ([PMID:27127721]). Subsequent screening of 25 young-onset parkinsonism patients identified four carriers of biallelic PLA2G6 variants (including homozygous c.991G>T (p.Asp331Tyr) and compound heterozygous c.991G>T/c.1077G>A), confirming PLA2G6 as the second most common YOPD locus after PRKN ([PMID:22213678]).

In a Chinese autosomal-recessive early-onset parkinsonism cohort, one family exhibited homozygous c.991G>T (p.Asp331Tyr) in two siblings, with PET showing reduced striatal DAT binding and in vitro assays demonstrating ~70% loss of enzyme activity in mutant PLA2G6 ([PMID:21700586]). A later compound heterozygous case (c.991G>T/c.1472+1G>A) presented with absent swallow-tail sign, cerebellar atrophy, and L-DOPA responsiveness, reinforcing the AR inheritance and phenotypic spectrum ([PMID:31496990]).

Overall, at least seven unrelated probands across three families harbor biallelic PLA2G6 variants (missense, splice-site, frameshift), with homozygous and compound heterozygous genotypes confirmed by segregation and functional characterization.

Functional studies demonstrate that PLA2G6 PARK14-associated missense variants abolish phospholipase activity, promote mitochondrial dysfunction, ROS production, and activation of apoptotic pathways in cellular models ([PMID:29108286]). Zebrafish and murine Pla2g6 deficiency recapitulate dopaminergic cell loss, motor deficits, and raised β-synuclein, which are alleviated by L-DOPA or docosahexaenoic acid supplementation, establishing a loss-of-function mechanism ([PMID:29344929]; [PMID:34520727]).

While heterozygous PLA2G6 variants were once proposed as PD risk factors, large burden analyses in Chinese cohorts found no significant enrichment of rare heterozygous variants in cases versus controls, arguing against dominant risk ([PMID:33279242]).

Collectively, genetic and experimental concordance supports a Strong clinical validity for PLA2G6 in AR Parkinson disease 14. Genetic testing for PLA2G6 biallelic variants should be considered in early-onset, L-DOPA-responsive parkinsonism, with implications for diagnosis, management, and therapeutic development.

Key Take-home: Biallelic PLA2G6 loss-of-function variants cause autosomal recessive PARK14, with robust clinical, segregation, and functional evidence supporting genetic testing in early-onset parkinsonism.

References

• Tremor and other hyperkinetic movements • 2016 • PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism PMID:27127721
• American Journal of Medical Genetics Part B • 2012 • PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease PMID:22213678
• Neurology • 2011 • PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort PMID:21700586
• Frontiers in Neurology • 2019 • Early-Onset Parkinson's Disease Caused by PLA2G6 Compound Heterozygous Mutation, a Case Report and Literature Review PMID:31496990
• Oncotarget • 2017 • PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway PMID:29108286
• Molecular Neurobiology • 2018 • Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways PMID:29344929
• Neurobiology of Aging • 2021 • Association of rare heterozygous PLA2G6 variants with the risk of Parkinson's disease PMID:33279242

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