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In the last few years,  NEK1  has been identified as a new gene related to amyotrophic lateral sclerosis (ALS). Loss-of-function variants have been mostly described, although several missense variants exist, which pathogenic relevance remains to be established. We attempted to determine the contribution of  NEK1  gene in an Italian cohort of 531 sporadic and familial amyotrophic lateral sclerosis (ALS) patients applying massive parallel sequencing technologies. We filtered results of  NEK1  gene and identified 20  NEK1  rare variants (MAF &lt; 0.01) in 22 patients. In particular, we found two novel frameshift variants (p.Glu929Asnfs * 12 and p.Val1030Ilefs * 23), 18 missense variants, including the p.Arg261His in three patients, and a novel variant in the start codon, the p.Met1?, which most likely impairs translation initiation. To clarify the role of  NEK1  missense variants we investigated NEK1 expression in primary fibroblast cultures. We obtained skin biopsies from four patients with  NEK1  variants and we assessed NEK1 expression by western blot and immunofluorescence. We detected a decrease in NEK1 expression in fibroblasts from patients with  NEK1  variants, suggesting that missense variants in  NEK1  gene may have a pathogenic role. Moreover, we observed additional variants in ALS related genes in seven patients with  NEK1  variants (32%), further supporting an oligogenic ALS model.

Novel variants and cellular studies on patients’ primary fibroblasts support a role for NEK1 missense variants in ALS pathogenesis