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.

scholarly journals The Genes, Proteins, and the Cell Biological Processes Underlying Emery-Dreifuss Muscular Dystrophy

2017 ◽  
Vol 6 (1) ◽  
pp. 14-18
Author(s):  
Elise Alexandra Kikis ◽  
Megan Elizabeth Mastey
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Autosomal Dominant ◽  
Nuclear Lamina ◽  
Autosomal Recessive Inheritance ◽  
Envelope Proteins ◽  
Lamin A ◽  
Dominant Form ◽  
Specific Effects ◽  
Autosomal Dominant Form

Emery-Dreifuss Muscular Dystrophy (EDMD) is a type of muscular dystrophy characterized by contractures, or shortening of muscles or joints in the elbows and Achilles tendons, muscle wasting and weakness as well as cardiomyopathy. There are two main forms of inherited EDMD, X-linked recessive and autosomal dominant. There is also a rarer form of autosomal recessive inheritance with only a few cases ever reported. The X-linked form of EDMD is caused by mutation of the STA gene that encodes the protein emerin, while the autosomal dominant form is caused by a missense mutation on the LMNA gene, which encodes lamin A/C proteins. Both emerin and lamin A/C are nuclear envelope proteins that interact with other proteins to create a connective network that attaches the nuclear lamina to the cytoskeleton. These nuclear envelope proteins interact via accessory proteins to chromatin and also thereby stimulate gene expression. The exact mechanism of how mutations in these genes lead to muscular dystrophy is not well understood. The “structural hypothesis,” states that the absence of these envelope proteins result in a weakened cell and would eventually end in nuclear disruption. The “gene regulatory hypothesis” states that emerin and lamin may be transcription factors whose absence results in tissue-specific effects. This review will addresses these hypotheses, describes what is known about the cell and molecular biology underlying EDMD and considers recent as advances in therapeutics.

The cell cycle dependent mislocalisation of emerin may contribute to the Emery-Dreifuss muscular dystrophy phenotype

2002 ◽  
Vol 115 (2) ◽  
pp. 341-354 ◽  
Author(s):  
Elizabeth A. L. Fairley ◽  
Andrew Riddell ◽  
Juliet A. Ellis ◽  
John Kendrick-Jones
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Transmembrane Domain ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Dependent ◽  
Mutant Forms

Emerin is the nuclear membrane protein defective in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). The majority of X-EDMD patients have no detectable emerin. However, there are cases that produce mutant forms of emerin, which can be used to study its function. Our previous studies have shown that the emerin mutants S54F, P183T, P183H, Del95-99, Del236-241 (identified in X-EDMD patients) are targeted to the nuclear membrane but to a lesser extent than wild-type emerin. In this paper, we have studied how the mislocalisation of these mutant emerins may affect nuclear functions associated with the cell cycle using flow cytometry and immunofluorescence microscopy. We have established that cells expressing the emerin mutant Del236-241 (a deletion in the transmembrane domain), which was mainly localised in the cytoplasm, exhibited an aberrant cell cycle length. Thereafter, by examining the intracellular localisation of endogenously expressed lamin A/C and exogenously expressed wild-type and mutant forms of emerin after a number of cell divisions, we determined that the mutant forms of emerin redistributed endogenous lamin A/C. The extent of lamin A/C redistribution correlated with the amount of EGFP-emerin that was mislocalised. The amount of EGFP-emerin mislocalized, in turn, was associated with alterations in the nuclear envelope morphology. The nuclear morphology and redistribution of lamin A/C was most severely affected in the cells expressing the emerin mutant Del236-241.It is believed that emerin is part of a novel nuclear protein complex consisting of the barrier-to-autointegration factor (BAF), the nuclear lamina, nuclear actin and other associated proteins. The data presented here show that lamin A/C localisation is dominantly directed by its interaction with certain emerin mutants and perhaps wild-type emerin as well. These results suggest that emerin links A-type lamins to the nuclear envelope and that the correct localisation of these nuclear proteins is important for maintaining cell cycle timing.

Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene

2001 ◽  
Vol 114 (24) ◽  
pp. 4459-4468 ◽  
Author(s):  
Corinne Vigouroux ◽  
Martine Auclair ◽  
Emmanuelle Dubosclard ◽  
Marcel Pouchelet ◽  
Jacqueline Capeau ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Primary Cultures ◽  
Ectopic Expression ◽  
Nuclear Pore ◽  
Lamin A ◽  
Nuclear Pore Complexes ◽  
Intermediate Filament Proteins ◽  
Partial Lipodystrophy ◽  
Nuclear Alterations ◽  
Pore Complexes

Dunnigan-type familial partial lipodystrophy (FPLD), characterized by an abnormal body fat redistribution with insulin resistance, is caused by missense heterozygous mutations in A-type lamins (lamins A and C). A- and B-type lamins are ubiquitous intermediate filament proteins that polymerize at the inner face of the nuclear envelope. We have analyzed primary cultures of skin fibroblasts from three patients harboring R482Q or R482W mutations. These cells were euploid and able to cycle and divide. A subpopulation of these cells had abnormal blebbing nuclei with A-type lamins forming a peripheral meshwork, which was frequently disorganized. Inner nuclear membrane protein emerin, an A-type lamin-binding protein, strictly colocalized with this abnormal meshwork. Cells from lipodystrophic patients often had other nuclear envelope defects, mainly consisting of nuclear envelope herniations that were deficient in B-type lamins, nuclear pore complexes, lamina-associated protein 2 beta, and chromatin. The mechanical properties of nuclear envelopes were altered, as judged from the extensive deformations observed in nuclei from heat-shocked cells, and from the low stringency of extraction of their components. These structural nuclear alterations were caused by the lamins A/C mutations, as the same changes were introduced in human control fibroblasts by ectopic expression of R482W mutated lamin A.

Dominant lamin A/C gene mutations can be associated with muscular dystrophy and peripheral neuropathy

2004 ◽  
Vol 9 (2) ◽  
pp. 113-113 ◽  
Author(s):  
S Benedetti ◽  
S Previtali ◽  
D Toniolo ◽  
S Iannaccone ◽  
B Sferrazza ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Lamin A
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