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.

Key words:

• Optineurin
• mutation
• exome sequencing
• Golgi fragmentation

Acknowledgements

The authors thank L. Adams, C. Cecere, and J. O’Connor for their assistance in compiling family information. This work was funded by the Motor Neurone Disease Research Institute of Australia (Bill Gole Postdoctoral Research Fellowship to KLW, scholarship top-ups to JAF and EPM and Grant-in-Aid to JPA), MND Australia (MND Leadership Grant to IPB), and National Health and Medical Research Council of Australia [1006141, 1030513, 1086887, 1095215].

Declaration of interest

The authors declare no conflicts of interest.