Mouse model carrying H222P- Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies

Arimura, Takuro; Helbling-Leclerc, Anne; Massart, Catherine; Varnous, Shaïda; Niel, Florence; Lacène, Emmanuelle; Fromes, Yves; Toussaint, Marcel; Mura, Anne-Marie; Keller, Dagmar I.; Amthor, Helge; Isnard, Richard; Malissen, Marie; Schwartz, Ketty; Bonne, Gisèle

doi:10.1093/hmg/ddi017

Cited by 300 publications

(366 citation statements)

References 57 publications

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“…Reproduced, with permission, from The Journal of Clinical Investigation [56]. Mis-sense mutation Postnatal death associated with muscular dystrophy and cardiomyopathy [24] Lmna Δ9/Δ9 Splicing mutation and inframe deletion of exon 9…”

Section: Discussionmentioning

confidence: 99%

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Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

104

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The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the Atype lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

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Section: Discussionmentioning

confidence: 99%

“…Female homozygotes also exhibit these pathologies but at a later stage and survive for longer. The Lmna H222P/H222P mice may represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition in both skeletal and cardiac musculature that is similar to the human disease [24].…”

Section: The A-type Laminopathiesmentioning

confidence: 99%

Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

104

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“…Furthermore, Lmna lco/lco fibroblasts from these mice display nuclear envelope with only very minimal alterations. The extrapolation of these results to human is hazardous since mouse models often exhibit differences compared to human laminopathies [36,37]. For example, two mutated H222P alleles are necessary to develop muscular dystrophy in mice, whereas the patients are heterozygous [36].…”

Section: Lamin C Mutants Form Aberrant Intranucleoplasmic Aggregates mentioning

confidence: 99%

“…The extrapolation of these results to human is hazardous since mouse models often exhibit differences compared to human laminopathies [36,37]. For example, two mutated H222P alleles are necessary to develop muscular dystrophy in mice, whereas the patients are heterozygous [36]. Similarly, the clinical phenotype of LmnaL530P/ L530P mice, harboring an Emery-Dreifuss mutation, is consistent with human progeria syndrome [38].…”

Section: Lamin C Mutants Form Aberrant Intranucleoplasmic Aggregates mentioning

confidence: 99%

Specific contribution of lamin A and lamin C in the development of laminopathies

Sylvius

Hathaway

Boudreau

et al. 2008

Experimental Cell Research

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Mutations in the lamin A/C gene are involved in multiple human disorders for which the pathophysiological mechanisms are partially understood. Conflicting results prevail regarding the organization of lamin A and C mutants within the nuclear envelope (NE) and on the interactions of each lamin to its counterpart. We over-expressed various lamin A and C mutants both independently and together in COS7 cells. When expressed alone, lamin A with cardiac/muscular disorder mutations forms abnormal aggregates inside the NE and not inside the nucleoplasm. Conversely, the equivalent lamin C organizes as intranucleoplasmic aggregates that never connect to the NE as opposed to wild type lamin C. Interestingly, the lamin C molecules present within these aggregates exhibit an abnormal increased mobility. When co-expressed, the complex formed by lamin A/C aggregates in the NE. Lamin A and C mutants for lipodystrophy behave similarly to the wild type. These findings reveal that lamins A and C may be differentially affected depending on the mutation. This results in multiple possible physiological consequences which likely contribute in the phenotypic variability of laminopathies. The inability of lamin C mutants to join the nuclear rim in the absence of lamin A is a potential pathophysiological mechanism for laminopathies.

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“…Although a skeletal myopathy predominates in two of these disorders, some patients develop cardiac electrophysiologic disease, progressive left ventricular dysfunction and heart failure (11). Electrophysiologic defects usually precede DCM (12), and may be the only manifestation of cardiac involvement (13)].…”

Section: Introductionmentioning

confidence: 99%

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Wolf

Wang

Alcalai

et al. 2008

Journal of Molecular and Cellular Cardiology

152

147

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Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna +/-mice. Despite one normal allele, Lmna +/-mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna +/-mice but by 4 weeks of age AV nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10 week-old Lmna +/-mice showed atrioventricular (AV) conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month old Lmna +/-mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna +/-mice revealed DCM; in some mice this occurred without Contact address: Charles I. Berul, M.D., Department of Cardiology -Children's Hospital, 300 Longwood Ave., Boston, MA 02115 USA, Phone: 617 355-6432, Fax: 617 566-5671, charles.berul@cardio.chboston.org. * These authors contributed equally to this publication. Disclosures: NonePublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript J Mol Cell Cardiol. Author manuscript; available in PMC 2010 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.

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Mouse model carrying H222P- Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies

Cited by 300 publications

References 57 publications

Mouse models of the laminopathies

Mouse models of the laminopathies

Specific contribution of lamin A and lamin C in the development of laminopathies

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

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