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Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations

BACKGROUND: In eukaryotes the genetic material is enclosed by a continuous membrane system, the nuclear envelope (NE). Along the NE specific proteins assemble to form meshworks and mutations in these proteins have been described in a group of human diseases called laminopathies. Laminopathies includ...

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Autores principales: Yang, Liu, Munck, Martina, Swaminathan, Karthic, Kapinos, Larisa E., Noegel, Angelika A., Neumann, Sascha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748058/
https://www.ncbi.nlm.nih.gov/pubmed/23977161
http://dx.doi.org/10.1371/journal.pone.0071850
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author Yang, Liu
Munck, Martina
Swaminathan, Karthic
Kapinos, Larisa E.
Noegel, Angelika A.
Neumann, Sascha
author_facet Yang, Liu
Munck, Martina
Swaminathan, Karthic
Kapinos, Larisa E.
Noegel, Angelika A.
Neumann, Sascha
author_sort Yang, Liu
collection PubMed
description BACKGROUND: In eukaryotes the genetic material is enclosed by a continuous membrane system, the nuclear envelope (NE). Along the NE specific proteins assemble to form meshworks and mutations in these proteins have been described in a group of human diseases called laminopathies. Laminopathies include lipodystrophies, muscle and cardiac diseases as well as metabolic or progeroid syndromes. Most laminopathies are caused by mutations in the LMNAgene encoding lamins A/C. Together with Nesprins (Nuclear Envelope Spectrin Repeat Proteins) they are core components of the LINC complex (Linker of Nucleoskeleton and Cytoskeleton). The LINC complex connects the nucleoskeleton and the cytoskeleton and plays a role in the transfer of mechanically induced signals along the NE into the nucleus, and its components have been attributed functions in maintaining nuclear and cellular organization as well as signal transduction. RESULTS: Here we narrowed down the interaction sites between lamin A and Nesprin-2 to aa 403–425 in lamin A and aa 6146–6347 in Nesprin-2. Laminopathic mutations in and around the involved region of lamin A (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate the interaction with Nesprin-2 and this may contribute to the disease phenotype. The most notable mutation is the lamin A mutation Q432X that alters LINC complex protein assemblies and causes chromosomal and transcription factor rearrangements. CONCLUSION: Mutations in Nesprin-2 and lamin A are characterised by complex genotype phenotype relations. Our data show that each mutation in LMNAanalysed here has a distinct impact on the interaction among both proteins that substantially explains how distinct mutations in widely expressed genes lead to the formation of phenotypically different diseases.
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spelling pubmed-37480582013-08-23 Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations Yang, Liu Munck, Martina Swaminathan, Karthic Kapinos, Larisa E. Noegel, Angelika A. Neumann, Sascha PLoS One Research Article BACKGROUND: In eukaryotes the genetic material is enclosed by a continuous membrane system, the nuclear envelope (NE). Along the NE specific proteins assemble to form meshworks and mutations in these proteins have been described in a group of human diseases called laminopathies. Laminopathies include lipodystrophies, muscle and cardiac diseases as well as metabolic or progeroid syndromes. Most laminopathies are caused by mutations in the LMNAgene encoding lamins A/C. Together with Nesprins (Nuclear Envelope Spectrin Repeat Proteins) they are core components of the LINC complex (Linker of Nucleoskeleton and Cytoskeleton). The LINC complex connects the nucleoskeleton and the cytoskeleton and plays a role in the transfer of mechanically induced signals along the NE into the nucleus, and its components have been attributed functions in maintaining nuclear and cellular organization as well as signal transduction. RESULTS: Here we narrowed down the interaction sites between lamin A and Nesprin-2 to aa 403–425 in lamin A and aa 6146–6347 in Nesprin-2. Laminopathic mutations in and around the involved region of lamin A (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate the interaction with Nesprin-2 and this may contribute to the disease phenotype. The most notable mutation is the lamin A mutation Q432X that alters LINC complex protein assemblies and causes chromosomal and transcription factor rearrangements. CONCLUSION: Mutations in Nesprin-2 and lamin A are characterised by complex genotype phenotype relations. Our data show that each mutation in LMNAanalysed here has a distinct impact on the interaction among both proteins that substantially explains how distinct mutations in widely expressed genes lead to the formation of phenotypically different diseases. Public Library of Science 2013-08-20 /pmc/articles/PMC3748058/ /pubmed/23977161 http://dx.doi.org/10.1371/journal.pone.0071850 Text en © 2013 Yang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yang, Liu
Munck, Martina
Swaminathan, Karthic
Kapinos, Larisa E.
Noegel, Angelika A.
Neumann, Sascha
Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title_full Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title_fullStr Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title_full_unstemmed Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title_short Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
title_sort mutations in lmna modulate the lamin a - nesprin-2 interaction and cause linc complex alterations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748058/
https://www.ncbi.nlm.nih.gov/pubmed/23977161
http://dx.doi.org/10.1371/journal.pone.0071850
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