Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb
Abstract Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine mode...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-0893-1 |
| _version_ | 1818334380771246080 |
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| author | Jenni M. Laitila Elyshia L. McNamara Catherine D. Wingate Hayley Goullee Jacob A. Ross Rhonda L. Taylor Robbert van der Pijl Lisa M. Griffiths Rachel Harries Gianina Ravenscroft Joshua S. Clayton Caroline Sewry Michael W. Lawlor Coen A. C. Ottenheijm Anthony J. Bakker Julien Ochala Nigel G. Laing Carina Wallgren-Pettersson Katarina Pelin Kristen J. Nowak |
| author_facet | Jenni M. Laitila Elyshia L. McNamara Catherine D. Wingate Hayley Goullee Jacob A. Ross Rhonda L. Taylor Robbert van der Pijl Lisa M. Griffiths Rachel Harries Gianina Ravenscroft Joshua S. Clayton Caroline Sewry Michael W. Lawlor Coen A. C. Ottenheijm Anthony J. Bakker Julien Ochala Nigel G. Laing Carina Wallgren-Pettersson Katarina Pelin Kristen J. Nowak |
| author_sort | Jenni M. Laitila |
| collection | DOAJ |
| description | Abstract Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb Y2303H, Y935X, has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications. |
| first_indexed | 2024-12-13T14:06:37Z |
| format | Article |
| id | doaj.art-091348b090194a35b6fa183d1b10a74b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-13T14:06:37Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-091348b090194a35b6fa183d1b10a74b2022-12-21T23:42:35ZengBMCActa Neuropathologica Communications2051-59602020-02-018111910.1186/s40478-020-0893-1Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in NebJenni M. Laitila0Elyshia L. McNamara1Catherine D. Wingate2Hayley Goullee3Jacob A. Ross4Rhonda L. Taylor5Robbert van der Pijl6Lisa M. Griffiths7Rachel Harries8Gianina Ravenscroft9Joshua S. Clayton10Caroline Sewry11Michael W. Lawlor12Coen A. C. Ottenheijm13Anthony J. Bakker14Julien Ochala15Nigel G. Laing16Carina Wallgren-Pettersson17Katarina Pelin18Kristen J. Nowak19Folkhälsan Institute of Genetics, Folkhälsan Research Center, BiomedicumHarry Perkins Institute of Medical Research, QEII Medical CentreSchool of Human Sciences, University of Western AustraliaHarry Perkins Institute of Medical Research, QEII Medical CentreCentre for Human and Applied Physiological Sciences / Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College LondonHarry Perkins Institute of Medical Research, QEII Medical CentreDepartment of Cellular and Molecular Medicine, University of ArizonaDepartment of Neuropathology, PathWest Anatomical PathologyHarry Perkins Institute of Medical Research, QEII Medical CentreHarry Perkins Institute of Medical Research, QEII Medical CentreHarry Perkins Institute of Medical Research, QEII Medical CentreDubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street HospitalDivision of Pediatric Pathology and Neuroscience Research Center, Medical College of WisconsinDepartment of Cellular and Molecular Medicine, University of ArizonaSchool of Human Sciences, University of Western AustraliaCentre for Human and Applied Physiological Sciences / Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College LondonHarry Perkins Institute of Medical Research, QEII Medical CentreFolkhälsan Institute of Genetics, Folkhälsan Research Center, BiomedicumFolkhälsan Institute of Genetics, Folkhälsan Research Center, BiomedicumHarry Perkins Institute of Medical Research, QEII Medical CentreAbstract Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb Y2303H, Y935X, has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.http://link.springer.com/article/10.1186/s40478-020-0893-1NebulinMurine modelNemaline myopathySkeletal muscleNeuromuscular diseaseCongenital myopathy |
| spellingShingle | Jenni M. Laitila Elyshia L. McNamara Catherine D. Wingate Hayley Goullee Jacob A. Ross Rhonda L. Taylor Robbert van der Pijl Lisa M. Griffiths Rachel Harries Gianina Ravenscroft Joshua S. Clayton Caroline Sewry Michael W. Lawlor Coen A. C. Ottenheijm Anthony J. Bakker Julien Ochala Nigel G. Laing Carina Wallgren-Pettersson Katarina Pelin Kristen J. Nowak Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb Acta Neuropathologica Communications Nebulin Murine model Nemaline myopathy Skeletal muscle Neuromuscular disease Congenital myopathy |
| title | Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb |
| title_full | Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb |
| title_fullStr | Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb |
| title_full_unstemmed | Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb |
| title_short | Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb |
| title_sort | nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in neb |
| topic | Nebulin Murine model Nemaline myopathy Skeletal muscle Neuromuscular disease Congenital myopathy |
| url | http://link.springer.com/article/10.1186/s40478-020-0893-1 |
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