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Original research
Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities
  1. François Muratet1,
  2. Elisa Teyssou1,
  3. Aude Chiot1,
  4. Séverine Boillée1,
  5. Christian S Lobsiger1,
  6. Delphine Bohl1,
  7. Beata Gyorgy1,
  8. Justine Guegan1,
  9. Yannick Marie1,
  10. Maria del Mar Amador1,2,
  11. Francois Salachas2,
  12. Vincent Meininger3,
  13. Emilien Bernard4,5,
  14. Jean-Christophe Antoine6,
  15. Jean-Philippe Camdessanché6,
  16. William Camu7,
  17. Cécile Cazeneuve8,
  18. Anne-Laure Fauret-Amsellem8,
  19. Eric Leguern1,8,
  20. Kevin Mouzat9,10,
  21. Claire Guissart9,10,
  22. Serge Lumbroso9,10,
  23. Philippe Corcia11,12,
  24. Patrick Vourc'h12,13,
  25. Aude-Marie Grapperon14,
  26. Shahram Attarian14,
  27. Annie Verschueren14,
  28. Danielle Seilhean1,15,
  29. Stéphanie Millecamps1
  1. 1 Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM,Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, Île de France, France
  2. 2 AP-HP, Département de Neurologie, Centre de référence SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, Île de France, France
  3. 3 Hôpital des Peupliers, Ramsay General Health Group, Paris, Île-de-France, France
  4. 4 Centre de référence SLA, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Université de Lyon, Bron, Auvergne-Rhône-Alpes, France
  5. 5 Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, Lyon, Auvergne-Rhône-Alpes, France
  6. 6 Service de Neurologie, Centre de Ressource et de Compétence SLA, Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne, Rhône-Alpes, France
  7. 7 Centre de référence SLA, Hôpital Gui de Chauliac, CHU de Montpellier, Université de Montpellier, Montpellier, Languedoc-Roussillon, France
  8. 8 Département de Génétique et Cytogénétique, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, APHP, Hôpital Pitié-Salpêtrière, Paris, Île-de-France, France
  9. 9 Laboratoire de Biochimie et Biologie Moleculaire, CHU Nimes, Nîmes, Languedoc-Roussillon, France
  10. 10 Motoneuron Disease: Pathophysiology and Therapy, INM, INSERM, Université de Montpellier, Montpellier, Languedoc-Roussillon, France
  11. 11 Centre de référence SLA, Département de Neurologie, CHRU Tours, Tours, Centre-Val de Loire, France
  12. 12 UMR 1253, Université de Tours, Inserm, Tours, Centre-Val de Loire, France
  13. 13 Service de Biochimie et Biologie Moléculaire, CHU Tours, Tours, Centre-Val de Loire, France
  14. 14 Centre de Référence pour les Maladies Neuromusculaire et la SLA, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille, CHU de Marseille, Marseille, Provence-Alpes-Côte d'Azur, France
  15. 15 Département de Neuropathologie, APHP, Hôpital Pitié-Salpêtrière, Paris, Île-de-France, France
  1. Correspondence to Dr Stéphanie Millecamps, Institut du Cerveau, CS21414, Paris 75651, France; stephanie.millecamps{at}


Objective Mutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.

Methods We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.

Results We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.

Conclusions Our results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Anonymised data, materials and detailed protocols are available from the corresponding author on reasonable request.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Anonymised data, materials and detailed protocols are available from the corresponding author on reasonable request.

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  • DS and SM are joint senior authors.

  • Contributors FM acquired, analysed and validated data and wrote original draft of the study ET, AC performed genetic and biochemical analyses SB, CSL, DB contributed to all drafts of the manuscript for intellectual content BG, JG, EL analysed genetic data M-D-MA, FS, VM, EB, J-CA, J-PC, WC, A-MG, SA, AV collected clinical and familial data YM, CC, A-LF-A, KM, CG, SL, PC, PV acquired genetic data DS, SM jointly supervised, designed, wrote and reviewed the study and acquired funding support. All authors have read and approved the revised version of the manuscript.

  • Funding FM and AC received a PhD grant from the Brain-Cognition-Behaviour Doctoral School, (ED3C) at Sorbonne University and ET was supported by a PhD Fellowship from AFM-Téléthon (#18145) during 3 years.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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