Expression of Lamin A Mutated in the Carboxyl-Terminal Tail Generates an Aberrant Nuclear Phenotype Similar to That Observed in Cells from Patients with Dunnigan-Type Partial Lipodystrophy and Emery-Dreifuss Muscular Dystrophy

2003 ◽  
Vol 282 (1) ◽  
pp. 14-23 ◽  
Author(s):  
C Favreau
Keyword(s):  
Muscular Dystrophy ◽  
Lamin A ◽  
Partial Lipodystrophy ◽  
Carboxyl Terminal ◽  
In Cells

Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations

2004 ◽  
Vol 30 (4) ◽  
pp. 444-450 ◽  
Author(s):  
A. Muchir ◽  
J. Medioni ◽  
M. Laluc ◽  
C. Massart ◽  
T. Arimura ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Gene Mutations ◽  
Lamin A ◽  
Partial Lipodystrophy

scholarly journals Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts

2004 ◽  
Vol 24 (4) ◽  
pp. 1481-1492 ◽  
Author(s):  
Catherine Favreau ◽  
Dominique Higuet ◽  
Jean-Claude Courvalin ◽  
Brigitte Buendia
Keyword(s):  
Muscular Dystrophy ◽  
Lamin A ◽  
Missense Mutations ◽  
In Vitro Differentiation ◽  
Partial Lipodystrophy ◽  
Frequent Mutations ◽  
Familial Partial Lipodystrophy ◽  
Low Levels ◽  
A Site

ABSTRACT Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD). Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.

Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy

2001 ◽  
Vol 114 (24) ◽  
pp. 4435-4445 ◽  
Author(s):  
Cecilia Östlund ◽  
Gisèle Bonne ◽  
Ketty Schwartz ◽  
Howard J. Worman
Keyword(s):  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Lamin A ◽  
Wild Type ◽  
Yeast Two Hybrid ◽  
Partial Lipodystrophy ◽  
Lamin B1 ◽  
The Stability ◽  
Mutant Forms ◽  
Two Hybrid

Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene, which encodes lamin A and lamin C. Mutations in this gene also give rise to limb girdle muscular dystrophy type 1B, dilated cardiomyopathy with atrioventricular conduction defect and Dunnigan-type partial lipodystrophy. The properties of the mutant lamins that cause muscular dystrophy, lipodystrophy and dilated cardiomyopathy are not known. We transfected C2C12 myoblasts with cDNA encoding wild-type lamin A and 15 mutant forms found in patients affected by these diseases. Immunofluorescence microscopy showed that four mutants, N195K, E358K, M371K and R386K, could have a dramatically aberrant localization, with decreased nuclear rim staining and formation of intranuclear foci. The distributions of endogenous lamin A/C, lamin B1 and lamin B2 were also altered in cells expressing these four mutants and three of them caused a loss of emerin from the nuclear envelope. In the yeast two-hybrid assay, the 15 lamin A mutants studied interacted with themselves and with wild-type lamin A and lamin B1. Pulse-chase experiments showed no decrease in the stability of several representative lamin A mutants compared with wild-type. These results indicate that some lamin A mutants causing disease can be aberrantly localized, partially disrupt the endogenous lamina and alter emerin localization, whereas others localize normally in transfected cells.

scholarly journals Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

2021 ◽  
Vol 22 (13) ◽  
pp. 6669
Author(s):  
Byongsun Lee ◽  
Seungjae Lee ◽  
Younggwang Lee ◽  
Yongjin Park ◽  
Jaekyung Shim
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Membrane ◽  
Target Genes ◽  
Janus Kinase ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Lamin A ◽  
Stat3 Signaling ◽  
Exact Function ◽  
Muscle Homeostasis

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates signal transducers and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

scholarly journals Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1947
Author(s):  
Alice-Anaïs Varlet ◽  
Emmanuèle Helfer ◽  
Catherine Badens
Keyword(s):  
Mechanical Properties ◽  
Signaling Pathways ◽  
Metabolic Disorders ◽  
Lamin A ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy ◽  
Atherosclerotic Cardiovascular Diseases ◽  
Almost All ◽  
Type V

Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

scholarly journals Dysfunctional polycomb transcriptional repression contributes to lamin A/C–dependent muscular dystrophy

2020 ◽  
Vol 130 (5) ◽  
pp. 2408-2421 ◽  
Author(s):  
Andrea Bianchi ◽  
Chiara Mozzetta ◽  
Gloria Pegoli ◽  
Federica Lucini ◽  
Sara Valsoni ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Transcriptional Repression ◽  
Lamin A
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