Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.

<h4>Background</h4>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. L...

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Autores principales:	Liu Yang, Martina Munck, Karthic Swaminathan, Larisa E Kapinos, Angelika A Noegel, Sascha Neumann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/be5a7a7122af45e9837089214e80377f
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spelling	oai:doaj.org-article:be5a7a7122af45e9837089214e80377f2021-11-18T08:58:48ZMutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.1932-620310.1371/journal.pone.0071850https://doaj.org/article/be5a7a7122af45e9837089214e80377f2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23977161/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Liu YangMartina MunckKarthic SwaminathanLarisa E KapinosAngelika A NoegelSascha NeumannPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71850 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Liu Yang Martina Munck Karthic Swaminathan Larisa E Kapinos Angelika A Noegel Sascha Neumann Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.
description	<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
format	article
author	Liu Yang Martina Munck Karthic Swaminathan Larisa E Kapinos Angelika A Noegel Sascha Neumann
author_facet	Liu Yang Martina Munck Karthic Swaminathan Larisa E Kapinos Angelika A Noegel Sascha Neumann
author_sort	Liu Yang
title	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_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_sort	mutations in lmna modulate the lamin a--nesprin-2 interaction and cause linc complex alterations.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/be5a7a7122af45e9837089214e80377f
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Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.

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