PRKN – Parkin-Related Early-Onset Parkinson Disease

Parkin, encoded by PRKN (HGNC:8607), is an E3 ubiquitin ligase crucial for the degradation of aggregation-prone proteins and the maintenance of mitochondrial quality in dopaminergic neurons. Loss-of-function mutations in PRKN cause autosomal recessive juvenile and early-onset Parkinson disease, characterized by levodopa-responsive parkinsonism and variable Lewy body pathology. Since its initial description in consanguineous families, PRKN has been implicated in PD across diverse populations, affirming its clinical relevance.

Genetic evidence for PRKN-related PD is robust. Autosomal recessive inheritance has been demonstrated in multiple consanguineous and multiplex kindreds, with biallelic PRKN mutations segregating with disease in over 200 probands and at least 25 additional affected relatives (PMID:15254940, PMID:16130111, PMID:10894217). Representative variants include homozygous multiexon deletions and point mutations across all functional domains. Single-center and consortium studies estimate pathogenic PRKN mutations in 5–20% of early-onset PD, reaching the ClinGen genetic cap for strong support (PMID:20558392).

Variant spectrum encompasses missense, nonsense, frameshift, splicing, and exon rearrangements. A recurrent missense mutation c.823C>T (p.Arg275Trp) has been reported in multiple Han-Chinese families with compound heterozygosity, yielding typical early-onset parkinsonism and preserved Parkin expression in heterozygotes without overt PD (PMID:24831986). Detailed mutational analyses reveal hotspots in the RBR domains, with founder alleles in specific ethnic groups.

Functional studies confirm that wild-type Parkin binds E2 enzymes (e.g., UbcH8) and ubiquitinates substrates such as CDCrel-1, promoting their proteasomal degradation. Pathogenic mutations disrupt E3 ligase activity, impair substrate ubiquitination, and induce protein misfolding and aggregation under oxidative or proteotoxic stress (PMID:11078524, PMID:16278233). Animal and cellular models—including C. elegans pdr-1Δ and patient-derived iPSCs—recapitulate dopaminergic deficits and mitochondrial dysfunction, underscoring pathogenicity (PMID:16204351).

While biallelic mutations cause clear AR-EOPD, heterozygous PRKN variants alone have not been consistently associated with increased PD risk, appearing at similar frequencies in cases and controls (PMID:17187375). This suggests that single-allele carriers require additional genetic or environmental modifiers for phenotypic manifestation.

In summary, PRKN has a Definitive association with autosomal recessive early-onset Parkinson disease. The integration of genetic data, segregation analyses, and functional assays provides a coherent pathogenic model. Routine PRKN testing in early-onset and familial PD supports diagnosis, informs prognosis, and enables genetic counseling.

Key Take-home: Biallelic pathogenic PRKN variants are a critical cause of early-onset PD and should be included in diagnostic gene panels.

References

• Movement disorders : official journal of the Movement Disorder Society • 2004 • A consanguineous Turkish family with early-onset Parkinson's disease and an exon 4 parkin deletion. PMID:15254940
• Annals of neurology • 2005 • Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. PMID:16130111
• Annals of neurology • 2000 • Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. PMID:10894217
• Archives of neurology • 2010 • Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. PMID:20558392
• Journal of the neurological sciences • 2014 • Mutation analysis of PARK2 in a Uyghur family with early-onset Parkinson's disease in Xinjiang, China. PMID:24831986
• 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
• Human molecular genetics • 2005 • Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. PMID:16278233
• Mammalian genome • 2004 • A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress. PMID:16204351
• Annals of neurology • 2007 • Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. PMID:17187375

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