scholarly journals Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 844 ◽  
Author(s):  
Anne T. Bertrand ◽  
Astrid Brull ◽  
Feriel Azibani ◽  
Louise Benarroch ◽  
Khadija Chikhaoui ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
In Silico Analysis ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Muscle Disorders ◽  
Severity Of The Disease ◽  
Type V ◽  
Tetramer Stability

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.

scholarly journals Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

2021 ◽  
Vol 22 (8) ◽  
pp. 4256
Author(s):  
Lorenzo Maggi ◽  
Manolis Mavroidis ◽  
Stelios Psarras ◽  
Yassemi Capetanaki ◽  
Giovanna Lattanzi
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Muscle ◽  
Intermediate Filament ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
Left Ventricular ◽  
Intermediate Filament Proteins ◽  
Muscle Disorders ◽  
Genes Encoding ◽  
Molecular Aspects

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

scholarly journals PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1735
Author(s):  
Spartaco Santi ◽  
Vittoria Cenni ◽  
Cristina Capanni ◽  
Giovanna Lattanzi ◽  
Elisabetta Mattioli
Keyword(s):  
Muscular Dystrophy ◽  
Early Phase ◽  
Myogenic Differentiation ◽  
Nuclear Lamina ◽  
Muscle Differentiation ◽  
Lamin A ◽  
Histone Deacetylase 2 ◽  
Muscle Gene Expression ◽  
Muscle Gene ◽  
Human Muscle Cells

Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamin A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.

scholarly journals Cellular and Animal Models of Striated Muscle Laminopathies

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 291 ◽  
Author(s):  
Hannah A. Nicolas ◽  
Marie-Andrée Akimenko ◽  
Frédérique Tesson
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Striated Muscle ◽  
Nuclear Lamina ◽  
The Other ◽  
Lamin A ◽  
Lmna Gene ◽  
Future Directions ◽  
Exon 10

The lamin A/C (LMNA) gene codes for nuclear intermediate filaments constitutive of the nuclear lamina. LMNA has 12 exons and alternative splicing of exon 10 results in two major isoforms—lamins A and C. Mutations found throughout the LMNA gene cause a group of diseases collectively known as laminopathies, of which the type, diversity, penetrance and severity of phenotypes can vary from one individual to the other, even between individuals carrying the same mutation. The majority of the laminopathies affect cardiac and/or skeletal muscles. The underlying molecular mechanisms contributing to such tissue-specific phenotypes caused by mutations in a ubiquitously expressed gene are not yet well elucidated. This review will explore the different phenotypes observed in established models of striated muscle laminopathies and their respective contributions to advancing our understanding of cardiac and skeletal muscle-related laminopathies. Potential future directions for developing effective treatments for patients with lamin A/C mutation-associated cardiac and/or skeletal muscle conditions will be discussed.

FHL1B Interacts with Lamin A/C and Emerin at the Nuclear Lamina and is Misregulated in Emery-Dreifuss Muscular Dystrophy

2016 ◽  
Vol 3 (4) ◽  
pp. 497-510 ◽  
Author(s):  
Esma Ziat ◽  
Kamel Mamchaoui ◽  
Maud Beuvin ◽  
Isabelle Nelson ◽  
Feriel Azibani ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Lamina ◽  
Lamin A

scholarly journals A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0169189 ◽  
Author(s):  
Alice Barateau ◽  
Nathalie Vadrot ◽  
Patrick Vicart ◽  
Ana Ferreiro ◽  
Michèle Mayer ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Cell Nucleus ◽  
Congenital Muscular Dystrophy ◽  
Lamin A

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.

scholarly journals Lamin A/C: Function in Normal and Tumor Cells

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3688
Author(s):  
Niina Dubik ◽  
Sabine Mai
Keyword(s):  
Nuclear Protein ◽  
Striated Muscle ◽  
Accelerated Aging ◽  
Lamin A ◽  
Muscle Disorders ◽  
Damage Repair ◽  
Telomere Protection ◽  
Aggressive Cancer ◽  
Prostate Cancers ◽  
Mechanical Insult

This review is focused on lamin A/C, a nuclear protein with multiple functions in normal and diseased cells. Its functions, as known to date, are summarized. This summary includes its role in maintaining a cell’s structural stability, cell motility, mechanosensing, chromosome organization, gene regulation, cell differentiation, DNA damage repair, and telomere protection. As lamin A/C has a variety of critical roles within the cell, mutations of the lamin A/C gene and incorrect processing of the protein results in a wide variety of diseases, ranging from striated muscle disorders to accelerated aging diseases. These diseases, collectively termed laminopathies, are also touched upon. Finally, we review the existing evidence of lamin A/C’s deregulation in cancer. Lamin A/C deregulation leads to various traits, including genomic instability and increased tolerance to mechanical insult, which can lead to more aggressive cancer and poorer prognosis. As lamin A/C’s expression in specific cancers varies widely, currently known lamin A/C expression in various cancers is reviewed. Additionally, Lamin A/C’s potential as a biomarker in various cancers and as an aid in more accurately diagnosing intermediate Gleason score prostate cancers is also discussed.

scholarly journals Dropped head related lamin a/c associated congenital muscular dystrophy case; previously defined as emerydreifuss muscular dystrophy

2020 ◽  
Vol 62 (1) ◽  
pp. 130
Author(s):  
Hande Tekin ◽  
Sanem Yılmaz ◽  
Hasan Tekgül ◽  
Sarenur Gökben ◽  
Gül Aktan
Keyword(s):  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Lamin A
Sign in / Sign up

Export Citation Format

Share Document