PARK7 – Parkinson disease

PARK7 (HGNC:16369) encodes DJ-1, a ubiquitous protein involved in oxidative stress response and mitochondrial homeostasis. Biallelic loss-of-function variants in PARK7 cause autosomal recessive early-onset Parkinson disease (PMID:12446870). The phenotype includes levodopa-responsive parkinsonism, often with early non-motor features such as cognitive impairment or spasticity.

Genetic evidence supports a strong gene–disease relationship. At least 8 unrelated probands with homozygous or compound heterozygous PARK7 variants have been reported, segregating in 3 consanguineous families and multiple sibships (PMID:15365989, PMID:16240358). The inheritance is autosomal recessive, with 7 additional affected relatives demonstrating co-segregation of biallelic variants across these pedigrees.

To date, missense, nonsense, frameshift, splice, and multi-exon deletion alleles have been described. A recurrent founder variant c.192G>C (p.Glu64Asp) was first identified in a Turkish kindred and shown to reduce DAT binding on PET (PMID:15365989). Other variants include p.L166P, p.T154K and p.D131ThrfsTer3, all resulting in DJ-1 instability or loss of antioxidant activity.

Functional studies elucidate a loss-of-function mechanism. Pathogenic DJ-1 mutants (e.g., L166P, E64D) display accelerated proteasomal degradation, impaired dimerization, and failure to scavenge reactive oxygen species in cellular assays (PMID:12851414, PMID:15502874). DJ-1 knockout mice exhibit age-dependent motor deficits and altered striatal dopamine reuptake, recapitulating key aspects of PD pathology (PMID:15799973).

There is no significant conflicting evidence; heterozygous carriers are typically asymptomatic, and no studies have refuted the biallelic requirement. Modifier effects of heterozygous variants remain under investigation but do not detract from the AR-EOPD association.

In summary, PARK7 has a definitive autosomal recessive association with early-onset Parkinson disease underpinned by robust segregation and concordant functional data. Genetic testing for PARK7 variants informs diagnosis, enables carrier screening in consanguineous families, and supports genotype-driven therapeutic strategies.

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 • L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system. PMID:12851414
• PLoS Biology • 2004 • DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PMID:15502874

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