PON2 – Amyotrophic Lateral Sclerosis

PON2 has been evaluated as a susceptibility locus for amyotrophic lateral sclerosis (ALS) through case–control and sequencing studies. A haplotype at the C-terminal portion of PON2, including the Cys311Ser variant, showed significant association with ALS in France (480 cases, 475 controls; p = 0.0075), Quebec (159 cases, 95 controls; p = 0.026), and combined cohorts (1,197 cases, 1,076 controls; p = 1.69 × 10⁻⁶) (PMID:18695162). Targeted sequencing identified rare coding variants, including c.286del (p.Arg96LeufsTer) in familial and sporadic cases (PMID:20582942) and c.677A>G (p.Asn226Ser) in an Indian cohort (1/154 cases; 5.36% of sALS; PMID:31432357). However, a large meta-analysis of 4,037 ALS cases and 4,609 controls found no significant association for the PON2 intronic marker rs10487132 (OR 1.08, p = 0.35) after correction (PMID:19321847). No familial segregation data are available.

Functional studies directly linking PON2 to ALS pathogenesis are lacking. PON2 deficiency in mice leads to impaired motor coordination on rotarod testing, increased oxidative stress, and region-specific transcriptomic changes in brain regions (PMID:34216730), consistent with a role in neuronal resilience. The absence of replication across independent case–control studies and limited mechanistic data yield a constrained assessment of clinical validity and functional impact.

Key take-home: PON2 variants may modulate ALS risk, but current genetic and functional data are insufficient for definitive clinical interpretation.

References

• Neurology • 2008 • Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden. PMID:18695162
• Neurology • 2009 • A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS. PMID:19321847
• Annals of Neurology • 2010 • Paraoxonase gene mutations in amyotrophic lateral sclerosis. PMID:20582942
• Neurogenetics • 2019 • Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients. PMID:31432357
• Neurotoxicology and Teratology • 2021 • Paraoxonase 2 deficiency in mice alters motor behavior and causes region-specific transcript changes in the brain. PMID:34216730

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