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Amyotrophic Lateral Sclerosis is a fatal neurodegenerative disorder of motor neurons. The paraoxonase gene cluster on chromosome 7, including PON3, was evaluated for ALS susceptibility in a combined cohort of 1,197 cases and 1,076 controls across France (480 cases/475 controls), Quebec (159/95), and Sweden (558/506). A multi-SNP haplotype encompassing the C-terminal region of PON2 with contributions from PON3 tagSNPs reached genome-wide significance in the pooled analysis (p = 1.69 × 10⁻⁶) (PMID:18695162). No individual PON3 coding variants or familial segregation have been reported in ALS patients.
Functional characterization of PON3 has demonstrated antioxidant lactonase activity in vitro, analogous to PON1, but no studies have directly assessed PON3 in ALS-relevant cellular or animal models. The hypothesis that impaired PON3-mediated detoxification of reactive oxygen species contributes to motor neuron vulnerability remains plausible yet untested. Larger sequencing efforts and mechanistic investigations are needed to clarify the role of PON3 in ALS pathogenesis.
Key take-home: Evidence for PON3 as an ALS susceptibility gene is limited and currently insufficient to support clinical genetic testing or risk stratification.
Gene–Disease AssociationLimitedSingle multi-population haplotype association including PON3 tagSNPs in 1,197 ALS cases vs 1,076 controls without replication or coding variant evidence (PMID:18695162) Genetic EvidenceLimitedOne case–control haplotype study implicating the PON cluster including PON3; no PON3-specific coding variants identified in ALS cohorts Functional EvidenceLimitedNo direct functional studies of PON3 in ALS; mechanistic plausibility via oxidative stress pathways untested |