Frontiers in Aging Neuroscience (Mar 2021)
Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype
- Frances Theunissen,
- Frances Theunissen,
- Ryan S. Anderton,
- Ryan S. Anderton,
- Ryan S. Anderton,
- Frank L. Mastaglia,
- Frank L. Mastaglia,
- Loren L. Flynn,
- Loren L. Flynn,
- Loren L. Flynn,
- Samantha J. Winter,
- Samantha J. Winter,
- Ian James,
- Richard Bedlack,
- Stuart Hodgetts,
- Stuart Hodgetts,
- Sue Fletcher,
- Sue Fletcher,
- Steve D. Wilton,
- Steve D. Wilton,
- Steve D. Wilton,
- Nigel G. Laing,
- Mandi MacShane,
- Merrilee Needham,
- Merrilee Needham,
- Merrilee Needham,
- Ann Saunders,
- Alan Mackay-Sim,
- Alan Mackay-Sim,
- Ze’ev Melamed,
- Ze’ev Melamed,
- John Ravits,
- Don W. Cleveland,
- Don W. Cleveland,
- Don W. Cleveland,
- P. Anthony Akkari,
- P. Anthony Akkari,
- P. Anthony Akkari,
- P. Anthony Akkari
Affiliations
- Frances Theunissen
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Frances Theunissen
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Ryan S. Anderton
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Ryan S. Anderton
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- Ryan S. Anderton
- School of Health Sciences, Institute for Health Research, The University of Notre Dame Australia, Fremantle, WA, Australia
- Frank L. Mastaglia
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Frank L. Mastaglia
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- Loren L. Flynn
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Loren L. Flynn
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Loren L. Flynn
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- Samantha J. Winter
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Samantha J. Winter
- School of Health Sciences, Institute for Health Research, The University of Notre Dame Australia, Fremantle, WA, Australia
- Ian James
- Institute for Immunology and Infectious Disease, Murdoch University, Perth, WA, Australia
- Richard Bedlack
- Department of Neurology, Duke University, Durham, NC, United States
- Stuart Hodgetts
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Stuart Hodgetts
- School of Human Sciences, University of Western Australia, Nedlands, WA, Australia
- Sue Fletcher
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Sue Fletcher
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- Steve D. Wilton
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Steve D. Wilton
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Steve D. Wilton
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- Nigel G. Laing
- Centre for Medical Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia
- Mandi MacShane
- Centre for Medical Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia
- Merrilee Needham
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- Merrilee Needham
- Faculty of Medicine, The University of Notre Dame Australia, Fremantle, WA, Australia
- Merrilee Needham
- 0Department of Neurology, Fiona Stanley Hospital, Murdoch, WA, Australia
- Ann Saunders
- 1Zinfandel Pharmaceuticals, Chapel Hill, NC, United States
- Alan Mackay-Sim
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- Alan Mackay-Sim
- 2Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia
- Ze’ev Melamed
- 3Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, United States
- Ze’ev Melamed
- 4Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
- John Ravits
- 5Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Don W. Cleveland
- 3Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, United States
- Don W. Cleveland
- 4Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
- Don W. Cleveland
- 6Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
- P. Anthony Akkari
- Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
- P. Anthony Akkari
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
- P. Anthony Akkari
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia
- P. Anthony Akkari
- Department of Neurology, Duke University, Durham, NC, United States
- DOI
- https://doi.org/10.3389/fnagi.2021.658226
- Journal volume & issue
-
Vol. 13
Abstract
ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.
Keywords
- amyotrophic lateral sclerosis
- genetic variant
- genetic association studies
- stathmin-2
- genetic marker
- structural variation
