PRKN – Autosomal Recessive Juvenile Parkinson Disease 2

PRKN, encoding the E3 ubiquitin ligase parkin, is robustly associated with autosomal recessive juvenile Parkinson disease 2 (MONDO:0010820). Biallelic loss-of-function variants result in early-onset, levodopa-responsive parkinsonism with typical motor features and variable peripheral neuropathy. This phenotype is distinguished from idiopathic Parkinson disease by onset <40 years and absence of Lewy bodies in most cases.

Genetic Evidence

Autosomal recessive inheritance is confirmed by homozygous and compound heterozygous PRKN mutations segregating in multiple pedigrees. In a cohort of 34 affected individuals from 18 unrelated families, four different homozygous intragenic deletions and one-base deletions accounted for 56% of alleles, all showing complete cosegregation (PMID:9851438). Rare nonsense variants such as c.931C>T (p.Gln311Ter) have been reported in unrelated probands, further supporting loss-of-function (PMID:9731209). Sensory neuropathy with hyporeflexia emerges in advanced stages (PMID:12781600).

Variant Spectrum

Pathogenic alleles include large exon deletions (exons 3–5, 3, 4, 5), frameshift indels, splice-site changes, and nonsense mutations. Missense variants cluster in the ubiquitin-like and RING domains, disrupting protein stability or catalytic activity. Founder alleles such as c.255delA in Spanish populations illustrate recurrent events.

Functional Evidence

Parkin acts as an E3 ubiquitin-protein ligase, targeting substrates (e.g., CDCrel-1) for proteasomal degradation. Familial mutations abolish E3 activity in vitro, impair self-ubiquitination, and disrupt substrate turnover (PMID:11078524). In Caenorhabditis elegans, pdr-1 deletion mutants exhibit parkin aggregation and heightened proteotoxic sensitivity, recapitulating human loss-of-function (PMID:16204351).

Conflicting Evidence

Heterozygous PRKN mutations may modestly increase risk for late-onset Parkinson disease, but carriers remain asymptomatic for ARJP (PMID:27177722).

Integration & Clinical Utility

Extensive genetic and experimental data classify the PRKN–ARJP association as Strong. PRKN testing is recommended for early-onset, autosomal recessive parkinsonism, guiding genetic counseling and informing therapeutic strategies aimed at restoring ubiquitin–proteasome function.

Key Take-home: PRKN loss-of-function variants cause autosomal recessive juvenile parkinsonism with clear diagnostic and mechanistic implications.

References

• Annals of neurology • 1998 • Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. PMID:9851438
• Biochemical and biophysical research communications • 1998 • Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene. PMID:9731209
• 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 • A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress. PMID:16204351

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