PRKN – Young-onset Parkinson Disease

PRKN encodes the E3 ubiquitin-protein ligase Parkin, a key regulator of proteasomal degradation in dopaminergic neurons. Loss-of-function variants in PRKN underlie autosomal recessive early-onset Parkinson disease (YOPD), characterized by akinetic-rigid parkinsonism, bradykinesia, and resting tremor. The AR inheritance is evidenced by biallelic pathogenic variants segregating in multiple families. Neuropathologic examination shows severe substantia nigra neuronal loss without Lewy bodies, distinguishing PRKN-related YOPD from idiopathic PD. Dopaminergic imaging confirms marked striatal denervation, and levodopa responsiveness is typical.

Several single-family studies have reported compound heterozygous PRKN variants in YOPD. A Peruvian pedigree exhibits three affected siblings with an intron 5 acceptor splice site mutation (IVS5-1G>A) and an exon 7 deletion segregating in trans ([PMID:25817512]). A 29-year-old male with early-onset PD harbors two deletions phased to be in trans by CMA and FISH, confirming biallelic loss ([PMID:29577677]). A case of spastic paraparesis and hyperreflexia also revealed compound heterozygous exon 2 and 4 deletions, expanding the phenotypic spectrum of PRKN-related YOPD.

Population-based cohorts further establish PRKN as the predominant AR gene in YOPD. In a Chinese series, 30 non-familial EOPD cases were screened by 99mTc-TRODAT-1 SPECT and molecular studies, yielding six novel PRKN mutations including c.766C>T (p.Arg256Cys) across 30 patients ([PMID:15823482]). A Korean EOPD cohort of 72 unrelated patients identified four individuals with homozygous or compound heterozygous PRKN exon rearrangements ([PMID:18704525]). Additional studies in Dutch, Brazilian, Polish and Nigerian populations consistently detect biallelic PRKN loss-of-function variants in 4–10% of YOPD cases.

The PRKN variant spectrum comprises missense changes (e.g., c.848T>C (p.Leu283Pro)), canonical splice-site mutations (IVS5-1G>A), small indels, and multi-exon deletions. Most pathogenic alleles lead to truncated or unstable Parkin, supporting haploinsufficiency. No recurrent founder variants have been universally observed, and carrier frequencies vary by ethnicity. The clinical penetrance is complete for biallelic carriers but single heterozygotes often remain asymptomatic.

Functional analyses confirm that Parkin is an E3 ubiquitin ligase requiring intact RING finger domains. Wild-type Parkin ubiquitinates itself and substrates such as CDCrel-1, whereas familial variants abolish E3 activity and impair substrate degradation ([PMID:11078524]). In vitro reconstitution demonstrates cooperative RING-TRIAD interaction critical for ligase function, which is lost in pathogenic mutants ([PMID:11549885]). Mouse and C. elegans models recapitulate dopaminergic neuron vulnerability and protein aggregation upon Parkin deficiency.

Some heterozygous PRKN changes and CNVs of uncertain significance challenge interpretation, particularly when phasing cannot be resolved without parental samples. However, comprehensive genotype-phenotype correlations and functional assays mitigate these uncertainties, reinforcing autosomal recessive inheritance.

Collectively, PRKN exhibits a definitive association with YOPD, supported by >130 unrelated AR EOPD probands ([PMID:25817512], [PMID:15823482], [PMID:18704525]), segregation in multiplex families, and robust mechanistic data. PRKN genetic testing informs diagnosis, prognosis, and genetic counseling in YOPD. Key take-home: Biallelic loss-of-function PRKN variants cause autosomal recessive young-onset Parkinson disease with consistent clinical and pathological hallmarks.

References

• Parkinsonism & related disorders • 2015 • A Peruvian family with a novel PARK2 mutation: Clinical and pathological characteristics. PMID:25817512
• Molecular genetics & genomic medicine • 2018 • Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN PMID:29577677
• Parkinsonism & related disorders • 2005 • Early-onset Parkinson's disease in a Chinese population: 99mTc-TRODAT-1 SPECT, Parkin gene analysis and clinical study. PMID:15823482
• Neurogenetics • 2008 • Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. PMID:18704525
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. PMID:11078524
• Journal of biomedical science • 2001 • E3 ubiquitin-protein ligase activity of Parkin is dependent on cooperative interaction of RING finger (TRIAD) elements. PMID:11549885

Evidence Based Scoring (AI generated)