Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb.

Autor:	Laitila JM; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland. jenni.laitila@helsinki.fi.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland. jenni.laitila@helsinki.fi.; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia. jenni.laitila@helsinki.fi., McNamara EL; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Wingate CD; School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia., Goullee H; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Ross JA; Centre 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 London, London, UK., Taylor RL; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., van der Pijl R; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, USA., Griffiths LM; Department of Neuropathology, PathWest Anatomical Pathology, Nedlands, Western Australia, Australia., Harries R; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Ravenscroft G; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Clayton JS; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Sewry C; Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, Guilford Street, London, UK.; Wolfson Centre of Inherited Neuromuscular Diseases, RJAH Orthopaedic Hospital, Oswestry, UK., Lawlor MW; Division of Pediatric Pathology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA., Ottenheijm CAC; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, USA., Bakker AJ; School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia., Ochala J; Centre 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 London, London, UK., Laing NG; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; Centre for Medical Research, University of Western Australia, Perth, Australia., Wallgren-Pettersson C; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Pelin K; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.; Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland., Nowak KJ; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.; School of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Western Australia, Nedlands, Australia.; Office of Population Health Genomics, Public and Aboriginal Health Division, Western Australian Department of Health, East Perth, Western Australia, Australia.
Jazyk:	angličtina
Zdroj:	Acta neuropathologica communications [Acta Neuropathol Commun] 2020 Feb 17; Vol. 8 (1), pp. 18. Date of Electronic Publication: 2020 Feb 17.
DOI:	10.1186/s40478-020-0893-1
Abstrakt:	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.
Databáze:	MEDLINE
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