PARK7 – Young-onset Parkinson disease

Autosomal recessive mutations in the PARK7 gene underlie a subset of early‐onset parkinsonism with disease onset typically before age 40. PARK7 encodes DJ-1, a ubiquitously expressed protein involved in oxidative stress response and mitochondrial homeostasis. Young‐onset Parkinson disease (YOPD; MONDO:0017279) is characterized by bradykinesia, rigidity and dopaminergic deficits, often with slow progression.

Homozygous or compound heterozygous loss‐of‐function variants in PARK7 have been reported in at least four unrelated YOPD probands. Initial reports identified a large homozygous deletion, a nonsense variant c.82C>T (p.Arg28Ter), and a frameshift c.105dup (p.Ala36fs) in three families (PMID:12446870). Subsequently, a Turkish kindred harbored a homozygous c.192G>C (p.Glu64Asp) variant associated with presynaptic dopaminergic loss on PET despite incomplete clinical penetrance in a sibling (PMID:15365989).

Segregation evidence is limited by small pedigree sizes and variable penetrance; no additional clinically affected relatives with homozygous PARK7 variants have been reported beyond the probands. Population screens in diverse cohorts (Korean, Italian, Polish, Asian) reveal extremely low carrier frequency of pathogenic DJ-1 alleles, underscoring genetic heterogeneity in YOPD.

Functional studies across multiple systems support a loss‐of‐function mechanism. Mutant DJ-1 proteins (e.g., p.Leu166Pro, p.Met26Ile, p.Glu64Asp) exhibit reduced stability, impaired dimerization, and accelerated proteasomal degradation. DJ-1 knockdown sensitizes neuronal cells to oxidative and ER stress, whereas wild‐type DJ-1 rescues dopaminergic cell death (e.g., hydrogen peroxide challenge, Pael receptor overexpression) (PMID:14652021; PMID:12446870). DJ‐1 null mice display age‐dependent motor deficits and altered striatal dopamine handling, recapitulating early parkinsonian features (PMID:15799973).

No studies have formally refuted a PARK7–YOPD association, but the rarity of DJ-1 mutations and incomplete clinical penetrance suggest additional modifiers. The cumulative genetic and experimental data yield a Strong gene–disease association: four unrelated probands with homozygous PARK7 variants and consistent in vitro and in vivo loss‐of‐function evidence.

Key take‐home: PARK7 testing is clinically actionable in early‐onset parkinsonism, enabling molecular diagnosis and family counseling for autosomal recessive YOPD.

References

• Science • 2003 • Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. PMID:12446870
• Human mutation • 2004 • Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). PMID:15365989
• Biochemical and biophysical research communications • 2003 • Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. PMID:14652021
• The Journal of biological chemistry • 2005 • Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. PMID:15799973

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