Frontiers in Genetics (Jul 2020)
Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy
- Chiara Passarelli,
- Chiara Passarelli,
- Rita Selvatici,
- Alberto Carrieri,
- Francesca Romana Di Raimo,
- Maria Sofia Falzarano,
- Fernanda Fortunato,
- Rachele Rossi,
- Volker Straub,
- Katie Bushby,
- Mojgan Reza,
- Irina Zharaieva,
- Adele D’Amico,
- Enrico Bertini,
- Luciano Merlini,
- Patrizia Sabatelli,
- Paola Borgiani,
- Giuseppe Novelli,
- Giuseppe Novelli,
- Sonia Messina,
- Marika Pane,
- Eugenio Mercuri,
- Mireille Claustres,
- Sylvie Tuffery-Giraud,
- Annemieke Aartsma-Rus,
- Annemieke Aartsma-Rus,
- Pietro Spitali,
- Peter A. C. T’Hoen,
- Peter A. C. T’Hoen,
- Hanns Lochmüller,
- Hanns Lochmüller,
- Hanns Lochmüller,
- Hanns Lochmüller,
- Hanns Lochmüller,
- Kristin Strandberg,
- Cristina Al-Khalili,
- Ekaterina Kotelnikova,
- Michael Lebowitz,
- Elena Schwartz,
- Francesco Muntoni,
- Francesco Muntoni,
- Francesco Muntoni,
- Chiara Scapoli,
- Alessandra Ferlini,
- Alessandra Ferlini
Affiliations
- Chiara Passarelli
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Chiara Passarelli
- U.O.C. Laboratory of Medical Genetics, Paediatric Hospital Bambino Gesù, IRCCS, Rome, Italy
- Rita Selvatici
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Alberto Carrieri
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
- Francesca Romana Di Raimo
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Maria Sofia Falzarano
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Fernanda Fortunato
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Rachele Rossi
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Volker Straub
- John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Katie Bushby
- John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Mojgan Reza
- John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Irina Zharaieva
- Dubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom
- Adele D’Amico
- Molecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, Paediatric Hospital Bambino Gesù, IRCCS, Rome, Italy
- Enrico Bertini
- Molecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, Paediatric Hospital Bambino Gesù, IRCCS, Rome, Italy
- Luciano Merlini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Patrizia Sabatelli
- IRCCS Rizzoli & Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy
- Paola Borgiani
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Giuseppe Novelli
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Giuseppe Novelli
- 0Istituto Neuromed, IRCCS, Pozzilli, Italy
- Sonia Messina
- 1Department of Clinical and Experimental Medicine, Nemo Sud Clinical Center, University of Messina, Messina, Italy
- Marika Pane
- 2Paediatric Neurology Unit, Centro Clinico Nemo, IRCCS Fondazione Policlinico A. Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy
- Eugenio Mercuri
- 2Paediatric Neurology Unit, Centro Clinico Nemo, IRCCS Fondazione Policlinico A. Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy
- Mireille Claustres
- 3Laboratory of Genetics of Rare Diseases, University of Montpellier, Montpellier, France
- Sylvie Tuffery-Giraud
- 3Laboratory of Genetics of Rare Diseases, University of Montpellier, Montpellier, France
- Annemieke Aartsma-Rus
- John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Annemieke Aartsma-Rus
- 4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
- Pietro Spitali
- 4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
- Peter A. C. T’Hoen
- 4Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
- Peter A. C. T’Hoen
- 5Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
- Hanns Lochmüller
- 6Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center – University of Freiburg, Freiburg, Germany
- Hanns Lochmüller
- 7Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Hanns Lochmüller
- 8Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
- Hanns Lochmüller
- 9Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- Hanns Lochmüller
- 0Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
- Kristin Strandberg
- 1Department of Systems Biology, School of Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, Stockholm, Sweden
- Cristina Al-Khalili
- 1Department of Systems Biology, School of Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, Stockholm, Sweden
- Ekaterina Kotelnikova
- 2Panacea Pharmaceuticals, Gaithersburg, MD, United States
- Michael Lebowitz
- 2Panacea Pharmaceuticals, Gaithersburg, MD, United States
- Elena Schwartz
- 3National Cancer Institute, Bethesda, MD, United States
- Francesco Muntoni
- Dubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom
- Francesco Muntoni
- 4NIH Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
- Francesco Muntoni
- 5Great Ormond Street Hospital Trust, London, United Kingdom
- Chiara Scapoli
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
- Alessandra Ferlini
- Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Alessandra Ferlini
- Dubowitz Neuromuscular Center, University College London Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom
- DOI
- https://doi.org/10.3389/fgene.2020.00605
- Journal volume & issue
-
Vol. 11
Abstract
BackgroundDuchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment.Methods and FindingsWe enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in the TNFRSF10A gene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N = 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results.ConclusionWe have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.
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