King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Pages (from-to)351.e1-351.e6
JournalNeurobiology of Aging
Volume106
DOIs
Accepted/In press2021
PublishedOct 2021

Bibliographical note

Funding Information: This work was supported by grants from the UK Academy of Medical Sciences Daniel Turnberg Travel Fellowship Scheme , the Israel ALS Research Association (IsrALS) , the Medical Research Foundation UK (MRF) , the Van Geest Foundation , the Motor Neuron Disease Association (MNDA) , the Noreen Murray Foundation and Imam Abdulrahman bin Faisal University . Funding Information: The authors duly acknowledge the IoPPN Genomics and Biomarker Facility, King's College London that processed SNP Chip data that contributed to this study. This work was supported by grants from the UK Academy of Medical Sciences Daniel Turnberg Travel Fellowship Scheme, the Israel ALS Research Association (IsrALS), the Medical Research Foundation UK (MRF), the Van Geest Foundation, the Motor Neuron Disease Association (MNDA), the Noreen Murray Foundation and Imam Abdulrahman bin Faisal University. Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454