APEX1 – Amyotrophic Lateral Sclerosis

APEX1 encodes the major apurinic/apyrimidinic endonuclease involved in base excision repair and redox regulation. In a cohort of 34 familial ALS (fALS) probands, a rare heterozygous missense variant c.22G>A (p.Gly8Arg) was identified in one pedigree and segregated with disease in that kindred, with affected individuals showing lower motor neuron onset and prolonged survival ([PMID:39604641]). This evidence supports an autosomal dominant inheritance pattern but is currently limited to a single family.

Functional studies using EGFP-fusion constructs demonstrated that p.Gly8Arg disrupts nuclear localization of APE1, aligning with the established requirement of its N-terminal residues for nuclear import and suggesting loss-of-function as the pathogenic mechanism ([PMID:39604641], [PMID:15942031]). Together, the genetic and experimental data provide limited clinical validity pending replication, but highlight APEX1 as a plausible neuroprotective factor in ALS.

References

• Acta Neurologica Belgica • 2025 • A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression. PMID:39604641
• Nucleic Acids Research • 2005 • Analysis of nuclear transport signals in the human apurinic/apyrimidinic endonuclease (APE1/Ref1). PMID:15942031

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