A recessive S174X mutation in Optineurin causes amyotrophic lateral sclerosis through a loss of function via allele-specific nonsense-mediated decay

Marc Gotkine, Martina de Majo, Chun Hao Wong, Simon D. Topp, Rachel Michaelson-Cohen, Silvina Epsztejn-Litman, Rachel Eiges, Yossef Lerner Y, Moein Kanaan, Hagar Mor Shaked, Nada Alahmady, Caroline Vance, Stephen J. Newhouse, Gerome Breen, Agnes L. Nishimura, Christopher E. Shaw, Bradley N. Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Loss of function (LoF) mutations in Optineurin can cause recessive amyotrophic lateral sclerosis (ALS) with some heterozygous LoF mutations associated with dominant ALS. The molecular mechanisms underlying the variable inheritance pattern associated with OPTN mutations have remained elusive. We identified that affected members of a consanguineous Middle Eastern ALS kindred possessed a novel homozygous p.S174X OPTN mutation. Analysis of these primary fibroblast lines from family members identified that the p.S174X mutation reduces OPTN mRNA expression in an allele-dependent fashion by nonsense mediated decay. Western blotting correlated a reduced expression in heterozygote carriers but a complete absence of OPTN protein in the homozygous carrier. This data suggests that the p.S174X truncation mutation causes recessive ALS through LoF. However, functional analysis detected a significant increase in mitophagy markers TOM20 and COXIV, and higher rates of mitochondrial respiration and ATP levels in heterozygous carriers only. This suggests that heterozygous LoF OPTN mutations may not be causative in a Mendelian manner but may potentially behave as contributory ALS risk factors.

Original languageEnglish
Pages (from-to)351.e1-351.e6
JournalNeurobiology of Aging
Volume106
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Allele
  • ALS (Amyotrophic Lateral Sclerosis)
  • LoF (loss of function)
  • NMD (nonsense mediated decay)
  • Optineurin

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