A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.