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Torelli S, Scaglioni D, Sardone V, et al. High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients. J Neuropathol Exp Neurol. 2021;80(10):955-965doi: 10.1093/jnen/nlab088.
Torelli, S., Scaglioni, D., Sardone, V., Ellis, M. J., Domingos, J., Jones, A., Feng, L., Chambers, D., Eastwood, D. M., Leturcq, F., Yaou, R. B., Urtizberea, A., Sabouraud, P., Barnerias, C., Stojkovic, T., Ricci, E., Beuvin, M., Bonne, G., Sewry, C. A., Willis, T., Kulshrestha, R., Tasca, G., Phadke, R., Morgan, J. E., & Muntoni, F. (2021). High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients. Journal of neuropathology and experimental neurology, 80(10), 955-965. https://doi.org/10.1093/jnen/nlab088
Torelli, Silvia, et al. "High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients." Journal of neuropathology and experimental neurology vol. 80,10 (2021): 955-965. doi: https://doi.org/10.1093/jnen/nlab088
Torelli S, Scaglioni D, Sardone V, Ellis MJ, Domingos J, Jones A, Feng L, Chambers D, Eastwood DM, Leturcq F, Yaou RB, Urtizberea A, Sabouraud P, Barnerias C, Stojkovic T, Ricci E, Beuvin M, Bonne G, Sewry CA, Willis T, Kulshrestha R, Tasca G, Phadke R, Morgan JE, Muntoni F. High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients. J Neuropathol Exp Neurol. 2021 Oct 26;80(10):955-965. doi: 10.1093/jnen/nlab088. PMID: 34498054; PMCID: PMC8557329.
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J Neuropathol Exp Neurol. 2021 Oct 26;80(10):955-965. doi: 10.1093/jnen/nlab088.

High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients.

Journal of neuropathology and experimental neurology

Silvia Torelli, Domenic Scaglioni, Valentina Sardone, Matthew J Ellis, Joana Domingos, Adam Jones, Lucy Feng, Darren Chambers, Deborah M Eastwood, France Leturcq, Rabah Ben Yaou, Andoni Urtizberea, Pascal Sabouraud, Christine Barnerias, Tanya Stojkovic, Enzo Ricci, Maud Beuvin, Gisele Bonne, Caroline A Sewry, Tracey Willis, Richa Kulshrestha, Giorgio Tasca, Rahul Phadke, Jennifer E Morgan, Francesco Muntoni

Affiliations

  1. From the Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.
  2. NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  3. Dubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology & Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  4. Department of Orthopaedics, Great Ormond Street Hospital, London, UK.
  5. The Royal National Orthopaedic Hospital, Stanmore and University College London, London, UK.
  6. APHP, Laboratoire de Génétique et Biologie Moléculaire, HUPC Hôpital Cochin, Paris, France.
  7. APHP-Sorbonne Université, Centre de Référence Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.
  8. Sorbonne Université, Inserm, Institut de Myologie, Center de Recherche en Myologie, Paris, France.
  9. APHP-Hôpital Marin de Hendaye, Hendaye, France.
  10. CHU de Reims-American Memorial Hospital, Reims, France.
  11. Department of Pediatric Neurology, Necker Enfants Maladies Hospital, Paris, France.
  12. Institute of Neurology, Catholic University, Rome, Italy.
  13. Wolfson Centre for Inherited Neuromuscular Diseases and Department of Musculoskeletal Histopathology, RJAH Orthopaedic Hospital, Oswestry, UK.
  14. UOC di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  15. Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK.
  16. School of Cancer Sciences, University of Southampton, Southampton, UK.

PMID: 34498054 PMCID: PMC8557329 DOI: 10.1093/jnen/nlab088

Abstract

Duchenne muscular dystrophy (DMD) is an incurable disease caused by out-of-frame DMD gene deletions while in frame deletions lead to the milder Becker muscular dystrophy (BMD). In the last decade several antisense oligonucleotides drugs have been developed to induce a partially functional internally deleted dystrophin, similar to that produced in BMD, and expected to ameliorate the disease course. The pattern of dystrophin expression and functionality in dystrophinopathy patients is variable due to multiple factors, such as molecular functionality of the dystrophin and its distribution. To benchmark the success of therapeutic intervention, a clear understanding of dystrophin expression patterns in dystrophinopathy patients is vital. Recently, several groups have used innovative techniques to quantify dystrophin in muscle biopsies of children but not in patients with milder BMD. This study reports on dystrophin expression using both Western blotting and an automated, high-throughput, image analysis platform in DMD, BMD, and intermediate DMD/BMD skeletal muscle biopsies. Our results found a significant correlation between Western blot and immunofluorescent quantification indicating consistency between the different methodologies. However, we identified significant inter- and intradisease heterogeneity of patterns of dystrophin expression in patients irrespective of the amount detected on blot, due to variability in both fluorescence intensity and dystrophin sarcolemmal circumference coverage. Our data highlight the heterogeneity of the pattern of dystrophin expression in BMD, which will assist the assessment of dystrophin restoration therapies.

© 2021 American Association of Neuropathologists, Inc.

Keywords: Becker muscular dystrophy; Duchenne muscular dystrophy; Dystrophin; High–throughput digital analysis; Muscle biopsy; Skeletal muscle

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