RYR1 mutations are a common cause of congenital myopathies with central nuclei
dc.contributor.author | Wilmshurst, J. M. | en_US |
dc.contributor.author | Lillis, S. | en_US |
dc.contributor.author | Zhou, H. | en_US |
dc.contributor.author | Pillay, K. | en_US |
dc.contributor.author | Henderson, H. | en_US |
dc.contributor.author | Kress, W. | en_US |
dc.contributor.author | Müller, C. R. | en_US |
dc.contributor.author | Ndondo, A. | en_US |
dc.contributor.author | Cloke, V. | en_US |
dc.contributor.author | Cullup, T. | en_US |
dc.contributor.author | Bertini, E. | en_US |
dc.contributor.author | Boennemann, C. | en_US |
dc.contributor.author | Straub, V. | en_US |
dc.contributor.author | Quinlivan, R. | en_US |
dc.contributor.author | Dowling, James J. | en_US |
dc.contributor.author | Sarraj, S. | en_US |
dc.contributor.author | Treves, S. | en_US |
dc.contributor.author | Abbs, S. | en_US |
dc.contributor.author | Manzur, A. Y. | en_US |
dc.contributor.author | Sewry, C. A. | en_US |
dc.contributor.author | Muntoni, F. | en_US |
dc.contributor.author | Jungbluth, H. | en_US |
dc.date.accessioned | 2010-11-03T15:21:16Z | |
dc.date.available | 2011-03-01T16:26:48Z | en_US |
dc.date.issued | 2010-11 | en_US |
dc.identifier.citation | Wilmshurst, J.M.; Lillis, S.; Zhou, H.; Pillay, K.; Henderson, H.; Kress, W.; MÜller, C.R.; Ndondo, A.; Cloke, V.; Cullup, T.; Bertini, E.; Boennemann, C.; Straub, V.; Quinlivan, R.; Dowling, J.J.; Sarraj, S.; Treves, S.; Abbs, S.; Manzur, A.Y.; Sewry, C.A.; Muntoni, F.; Jungbluth, H. (2010). " RYR1 mutations are a common cause of congenital myopathies with central nuclei J.M.W. and S.L. contributed equally to the manuscript. ." Annals of Neurology 68(5): 717-726. <http://hdl.handle.net/2027.42/78229> | en_US |
dc.identifier.issn | 0364-5134 | en_US |
dc.identifier.issn | 1531-8249 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/78229 | |
dc.description.abstract | Objective Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. Methods We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. Results The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. Interpretation Our findings expand the range of RYR1 -related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.ANN NEUROL 2010 | en_US |
dc.format.extent | 514546 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | Life and Medical Sciences | en_US |
dc.subject.other | Neuroscience, Neurology, and Psychiatry | en_US |
dc.title | RYR1 mutations are a common cause of congenital myopathies with central nuclei | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Psychiatry | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan, USA | en_US |
dc.contributor.affiliationother | Department of Paediatric Neurology, School of Child and Adolescent Health, University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa | en_US |
dc.contributor.affiliationother | Diagnostics Genetics Laboratory, GSTS Pathology, Guy's Hospital, London, UK | en_US |
dc.contributor.affiliationother | Dubowitz Neuromuscular Centre, Institute of Child Health, London, UK | en_US |
dc.contributor.affiliationother | Department of Paediatric Pathology, School of Child and Adolescent Health, University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa | en_US |
dc.contributor.affiliationother | Molecular Genetics Department, University of Cape Town, South Africa | en_US |
dc.contributor.affiliationother | Institute of Human Genetics, University of Wuerzburg, Biozentrum, Germany | en_US |
dc.contributor.affiliationother | Institute of Human Genetics, University of Wuerzburg, Biozentrum, Germany | en_US |
dc.contributor.affiliationother | Department of Paediatric Neurology, School of Child and Adolescent Health, University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa | en_US |
dc.contributor.affiliationother | Diagnostics Genetics Laboratory, GSTS Pathology, Guy's Hospital, London, UK | en_US |
dc.contributor.affiliationother | Diagnostics Genetics Laboratory, GSTS Pathology, Guy's Hospital, London, UK | en_US |
dc.contributor.affiliationother | Unit of Molecular Medicine, Ospedale Bambino GesÙ, Rome, Italy | en_US |
dc.contributor.affiliationother | Department of Paediatric Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA | en_US |
dc.contributor.affiliationother | Institute for Human Genetics, International Centre for Life, University of Newcastle upon Tyne, Newcastle upon Tyne, UK | en_US |
dc.contributor.affiliationother | Centre for Inherited Neuromuscular Disorders, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK | en_US |
dc.contributor.affiliationother | Department of Clinical Neuropathology, King's College Hospital, London, UK | en_US |
dc.contributor.affiliationother | Departments of Anaesthesia and Research, Basel University Hospital, Basel, Switzerland | en_US |
dc.contributor.affiliationother | Diagnostics Genetics Laboratory, GSTS Pathology, Guy's Hospital, London, UK | en_US |
dc.contributor.affiliationother | Dubowitz Neuromuscular Centre, Institute of Child Health, London, UK | en_US |
dc.contributor.affiliationother | Dubowitz Neuromuscular Centre, Institute of Child Health, London, UK ; Centre for Inherited Neuromuscular Disorders, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK | en_US |
dc.contributor.affiliationother | Dubowitz Neuromuscular Centre, Institute of Child Health, London, UK | en_US |
dc.contributor.affiliationother | Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London, UK ; Clinical Neuroscience Division, IOP, King's College, London, UK ; Department of Clinical Neurosciences, IOP, King's College London, and Department of Paediatric Neurology, Evelina Children's Hospital, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK | en_US |
dc.identifier.pmid | 20839240 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/78229/1/22119_ftp.pdf | |
dc.identifier.doi | 10.1002/ana.22119 | en_US |
dc.identifier.source | Annals of Neurology | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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