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

Paolo Niccolo' Doronzio, Giuseppe Marangi, Marcella Zollino, Mario Sabatelli, Serena Lattante, Francesco Martello, Emiliana Meleo, Angela Romano, Amelia Conte, Giulia Bisogni, Davide Colavito, Elda Del Giudice, Agata Katia Patanella, Daniela Bernardo

Research output: Contribution to journalArticle

Abstract

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 <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.
Original languageEnglish
Pages (from-to)N/A-N/A
JournalHUMAN MOLECULAR GENETICS
DOIs
Publication statusPublished - 2021

Keywords

  • Amyotrophic lateral sclerosis
  • NEK1

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