A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1%) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin. We identified a novel heterozygous missense mutation in OPTN (c.883G > T, p.Val295Phe) in a single familial ALS case. This mutation induced recognized cellular features of ALS pathogenesis including Golgi fragmentation and ER stress in NSC-34 cells. In conclusion, the identification of a novel OPTN mutation in an Australian ALS family, and its capacity to induce ALS-like pathological features in vitro, further strengthens evidence for the role of optineurin in the pathogenesis of ALS.

LanguageEnglish
Pages126-133
Number of pages8
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume18
Issue number1-2
DOIs
Publication statusPublished - 2 Jan 2017

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Amyotrophic Lateral Sclerosis
Mutation
Genes
In Vitro Techniques

Keywords

  • exome sequencing
  • Golgi fragmentation
  • mutation
  • Optineurin

Cite this

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title = "A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro",
abstract = "Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1{\%}) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin. We identified a novel heterozygous missense mutation in OPTN (c.883G > T, p.Val295Phe) in a single familial ALS case. This mutation induced recognized cellular features of ALS pathogenesis including Golgi fragmentation and ER stress in NSC-34 cells. In conclusion, the identification of a novel OPTN mutation in an Australian ALS family, and its capacity to induce ALS-like pathological features in vitro, further strengthens evidence for the role of optineurin in the pathogenesis of ALS.",
keywords = "exome sequencing, Golgi fragmentation, mutation, Optineurin",
author = "Fifita, {Jennifer A.} and Williams, {Kelly L.} and Vinod Sundaramoorthy and Mccann, {Emily P.} and Nicholson, {Garth A.} and Atkin, {Julie D.} and Blair, {Ian P.}",
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language = "English",
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A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro. / Fifita, Jennifer A.; Williams, Kelly L.; Sundaramoorthy, Vinod; Mccann, Emily P.; Nicholson, Garth A.; Atkin, Julie D.; Blair, Ian P.

In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Vol. 18, No. 1-2, 02.01.2017, p. 126-133.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro

AU - Fifita, Jennifer A.

AU - Williams, Kelly L.

AU - Sundaramoorthy, Vinod

AU - Mccann, Emily P.

AU - Nicholson, Garth A.

AU - Atkin, Julie D.

AU - Blair, Ian P.

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N2 - Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1%) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin. We identified a novel heterozygous missense mutation in OPTN (c.883G > T, p.Val295Phe) in a single familial ALS case. This mutation induced recognized cellular features of ALS pathogenesis including Golgi fragmentation and ER stress in NSC-34 cells. In conclusion, the identification of a novel OPTN mutation in an Australian ALS family, and its capacity to induce ALS-like pathological features in vitro, further strengthens evidence for the role of optineurin in the pathogenesis of ALS.

AB - Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1%) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin. We identified a novel heterozygous missense mutation in OPTN (c.883G > T, p.Val295Phe) in a single familial ALS case. This mutation induced recognized cellular features of ALS pathogenesis including Golgi fragmentation and ER stress in NSC-34 cells. In conclusion, the identification of a novel OPTN mutation in an Australian ALS family, and its capacity to induce ALS-like pathological features in vitro, further strengthens evidence for the role of optineurin in the pathogenesis of ALS.

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