Rocío N Villar-Quiles1,2, Fabio Catervi1, Eva Cabet1, Raul Juntas-Morales3, Casie A Genetti4, Teresa Gidaro5, Asuman Koparir6, Adnan Yüksel6, Sandra Coppens7, Nicolas Deconinck7, Emma Pierce-Hoffman8, Xavière Lornage9, Julien Durigneux10, Jocelyn Laporte9, John Rendu11, Norma B Romero2,12, Alan H Beggs4, Laurent Servais5,13, Mireille Cossée14, Montse Olivé15, Johann Böhm9, Isabelle Duband-Goulet1, Ana Ferreiro1,2. 1. Basic and Translational Myology Laboratory, UMR8251, University of Paris/National Center for Scientific Research, Paris, France. 2. Reference Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, APHP, Institute of Myology, Paris, France. 3. Neuromuscular Unit, University Hospital Center Montpellier/EA7402 University of Montpellier, University Institute of Clinical Research, Montpellier, France. 4. Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA. 5. I-Motion, Institute of Myology, APHP, Paris, France. 6. Department of Molecular Biology and Genetics, Biruni University, Istanbul, Turkey. 7. Department of Pediatric Neurology, Reference Neuromuscular Center, Queen Fabiola Children's University Hospital, Free University of Brussels, Brussels, Belgium. 8. Center for Mendelian Genomics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA. 9. Department of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology, National Institute of Health and Medical Research U1258, National Center for Scientific Research UMR7104, University of Strasbourg, Illkirch, France. 10. Department of Neuropediatrics, University Hospital Center Angers, Neuromuscular Diseases Reference Center Antlantique Occitanie Caraïbe, Angers, France. 11. Laboratory of Biochemistry and Molecular Genetics, University Hospital Center Grenoble, Grenoble, France. 12. Neuromuscular Morphology Unit, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France. 13. Division of Child Neurology, Neuromuscular Diseases Reference Center, Department of Pediatrics, Liège University Hospital and University of Liège, Liège, Belgium. 14. Molecular Genetics Laboratory, University Hospital Center Montpellier/National Institute of Health and Medical Research U827, University Institute of Clinical Research, Montpellier, France. 15. Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Institute of Biomedical Research of Bellvitge-University Hospital of Bellvitge, Barcelona, Spain.
Abstract
OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. METHODS: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. RESULTS: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. INTERPRETATION: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.
OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. METHODS: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. RESULTS: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. INTERPRETATION: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.
Authors: M Scoto; S Cirak; R Mein; L Feng; A Y Manzur; S Robb; A-M Childs; R M Quinlivan; H Roper; D H Jones; C Longman; G Chow; M Pane; M Main; M G Hanna; K Bushby; C Sewry; S Abbs; E Mercuri; F Muntoni Journal: Neurology Date: 2011-06-14 Impact factor: 9.910
Authors: Sebastian Schafer; Antonio de Marvao; Eleonora Adami; Lorna R Fiedler; Benjamin Ng; Ester Khin; Owen J L Rackham; Sebastiaan van Heesch; Chee J Pua; Miao Kui; Roddy Walsh; Upasana Tayal; Sanjay K Prasad; Timothy J W Dawes; Nicole S J Ko; David Sim; Laura L H Chan; Calvin W L Chin; Francesco Mazzarotto; Paul J Barton; Franziska Kreuchwig; Dominique P V de Kleijn; Teresa Totman; Carlo Biffi; Nicole Tee; Daniel Rueckert; Valentin Schneider; Allison Faber; Vera Regitz-Zagrosek; Jonathan G Seidman; Christine E Seidman; Wolfgang A Linke; Jean-Paul Kovalik; Declan O'Regan; James S Ware; Norbert Hubner; Stuart A Cook Journal: Nat Genet Date: 2016-11-21 Impact factor: 38.330
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