Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy
<i>LMNA</i> 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 mech...
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doaj-097506a7f14b45929ed09aaf7d16047b2020-11-25T02:28:44ZengMDPI AGCells2073-44092020-03-01984484410.3390/cells9040844Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular DystrophyAnne T. Bertrand0Astrid Brull1Feriel Azibani2Louise Benarroch3Khadija Chikhaoui4Colin L. Stewart5Ohad Medalia6Rabah Ben Yaou7Gisèle Bonne8Institut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, FranceInstitut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, FranceInstitut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, FranceInstitut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, FranceNeuromuscular Reference Center Nord-Est-Île de France, Institut de Myologie, G.H. Pitié Salpêtrière, F-75651 Paris CEDEX 13, FranceInstitute of Medical Biology, Immunos 81 Biomedical Grove, Singapore 138648, SingaporeDepartment of Biochemistry, University of Zurich, CH-8057 Zurich, SwitzerlandInstitut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, FranceInstitut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, INSERM UMRS974, F-75651 Paris CEDEX 13, France<i>LMNA</i> 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. <i>LMNA</i> mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and <i>LMNA</i>-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-<i>LMNA</i> 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.https://www.mdpi.com/2073-4409/9/4/844Emery–Dreifuss muscular dystrophy<i>LMNA</i>-related congenital muscular dystrophyLamin A/C<i>LMNA</i> |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anne T. Bertrand Astrid Brull Feriel Azibani Louise Benarroch Khadija Chikhaoui Colin L. Stewart Ohad Medalia Rabah Ben Yaou Gisèle Bonne |
spellingShingle |
Anne T. Bertrand Astrid Brull Feriel Azibani Louise Benarroch Khadija Chikhaoui Colin L. Stewart Ohad Medalia Rabah Ben Yaou Gisèle Bonne Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy Cells Emery–Dreifuss muscular dystrophy <i>LMNA</i>-related congenital muscular dystrophy Lamin A/C <i>LMNA</i> |
author_facet |
Anne T. Bertrand Astrid Brull Feriel Azibani Louise Benarroch Khadija Chikhaoui Colin L. Stewart Ohad Medalia Rabah Ben Yaou Gisèle Bonne |
author_sort |
Anne T. Bertrand |
title |
Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy |
title_short |
Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy |
title_full |
Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy |
title_fullStr |
Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy |
title_full_unstemmed |
Lamin A/C Assembly Defects in <i>LMNA</i>-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy |
title_sort |
lamin a/c assembly defects in <i>lmna</i>-congenital muscular dystrophy is responsible for the increased severity of the disease compared with emery–dreifuss muscular dystrophy |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-03-01 |
description |
<i>LMNA</i> 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. <i>LMNA</i> mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and <i>LMNA</i>-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-<i>LMNA</i> 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. |
topic |
Emery–Dreifuss muscular dystrophy <i>LMNA</i>-related congenital muscular dystrophy Lamin A/C <i>LMNA</i> |
url |
https://www.mdpi.com/2073-4409/9/4/844 |
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