| Autor: |
Bugiardini E; Queen Square Centre for Neuromuscular Diseases Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery London United Kingdom., Nunes AM; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV., Oliveira-Santos A; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV., Dagda M; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV., Fontelonga TM; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV., Barraza-Flores P; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV., Pittman AM; Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London United Kingdom.; St George's University of London London United Kingdom., Morrow JM; Queen Square Centre for Neuromuscular Diseases Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery London United Kingdom., Parton M; Queen Square Centre for Neuromuscular Diseases Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery London United Kingdom., Houlden H; Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London United Kingdom., Elliott PM; Barts Heart Centre, Barts Health NHS Trust London United Kingdom.; Centre for Heart Muscle Disease Institute of Cardiovascular Science, University College London London United Kingdom., Syrris P; Centre for Heart Muscle Disease Institute of Cardiovascular Science, University College London London United Kingdom., Maas RP; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center Nijmegen The Netherlands., Akhtar MM; Barts Heart Centre, Barts Health NHS Trust London United Kingdom.; Centre for Heart Muscle Disease Institute of Cardiovascular Science, University College London London United Kingdom., Küsters B; Department of Pathology Radboud University Medical Center Nijmegen The Netherlands., Raaphorst J; Department of Neurology, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam Neuroscience Amsterdam The Netherlands., Schouten M; Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands., Kamsteeg EJ; Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands., van Engelen B; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center Nijmegen The Netherlands., Hanna MG; Queen Square Centre for Neuromuscular Diseases Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery London United Kingdom., Phadke R; Division of Neuropathology UCL Institute of Neurology London United Kingdom.; Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases UCL Great Ormond Street Institute of Child Health London United Kingdom., Lopes LR; Barts Heart Centre, Barts Health NHS Trust London United Kingdom.; Centre for Heart Muscle Disease Institute of Cardiovascular Science, University College London London United Kingdom., Matthews E; The Atkinson Morley Neuromuscular Centre and Regional Neurosciences Centre St George's University Hospitals NHS Foundation Trust London United Kingdom.; Molecular and Clinical Sciences Research Institute, St George's University of London London United Kingdom., Burkin DJ; Department of Pharmacology University of Nevada Reno, School of Medicine, Center for Molecular Medicine Reno NV. |
| Abstrakt: |
Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene ( ITGA7 ) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7 -/- mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7 -/- mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7 -related congenital myopathy. |
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