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Article: Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells

TitleNesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells
Authors
Issue Date2007
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2007, v. 16 n. 23, p. 2944-2959 How to Cite?
AbstractThe S143F lamin A/C point mutation causes a phenotype combining features of myopathy and progeria. We demonstrate here that patient dermal fibroblast cells have dysmorphic nuclei containing numerous blebs and lobulations, which progressively accumulate as cells age in culture. The lamin A/C organization is altered, showing intranuclear and nuclear envelope (NE) aggregates and presenting often a honeycomb appearance. Immunofluorescence microscopy showed that nesprin-2 C-terminal isoforms and LAP2α were recovered in the cytoplasm, whereas LAP2β and emerin were unevenly localized along the NE. In addition, the intranuclear organization of acetylated histones, histone H1 and the active form of RNA polymerase II were markedly different in patient cells. A subpopulation of mutant cells, however, expressing the 800 kDa nesprin-2 giant isoform, did not show an overt nuclear phenotype. Ectopic expression of p.S143F lamin A in fibroblasts recapitulates the patient cell phenotype, whereas no effects were observed in p.S143F LMNA keratinocytes, which highly express nesprin-2 giant. Overexpression of the mutant lamin A protein had a more severe impact on the NE of nesprin-2 giant deficient fibroblasts when compared with wild-type. In summary, our results suggest that the p.S143F lamin A mutation affects NE architecture and composition, chromatin organization, gene expression and transcription. Furthermore, our findings implicate a direct involvement of the nesprins in laminopathies and propose nesprin-2 giant as a structural reinforcer at the NE. © The Author 2007. Published by Oxford University Press. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/68192
ISSN
2015 Impact Factor: 5.985
2015 SCImago Journal Rankings: 4.288
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKandert, Sen_HK
dc.contributor.authorLüke, Yen_HK
dc.contributor.authorKleinhenz, Ten_HK
dc.contributor.authorNeumann, Sen_HK
dc.contributor.authorLu, Wen_HK
dc.contributor.authorJaeger, VMen_HK
dc.contributor.authorMunck, Men_HK
dc.contributor.authorWehnert, Men_HK
dc.contributor.authorMüller, CRen_HK
dc.contributor.authorZhou, Zen_HK
dc.contributor.authorNoegel, AAen_HK
dc.contributor.authorDabauvalle, MCen_HK
dc.contributor.authorKarakesisoglou, Ien_HK
dc.date.accessioned2010-09-06T06:02:14Z-
dc.date.available2010-09-06T06:02:14Z-
dc.date.issued2007en_HK
dc.identifier.citationHuman Molecular Genetics, 2007, v. 16 n. 23, p. 2944-2959en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68192-
dc.description.abstractThe S143F lamin A/C point mutation causes a phenotype combining features of myopathy and progeria. We demonstrate here that patient dermal fibroblast cells have dysmorphic nuclei containing numerous blebs and lobulations, which progressively accumulate as cells age in culture. The lamin A/C organization is altered, showing intranuclear and nuclear envelope (NE) aggregates and presenting often a honeycomb appearance. Immunofluorescence microscopy showed that nesprin-2 C-terminal isoforms and LAP2α were recovered in the cytoplasm, whereas LAP2β and emerin were unevenly localized along the NE. In addition, the intranuclear organization of acetylated histones, histone H1 and the active form of RNA polymerase II were markedly different in patient cells. A subpopulation of mutant cells, however, expressing the 800 kDa nesprin-2 giant isoform, did not show an overt nuclear phenotype. Ectopic expression of p.S143F lamin A in fibroblasts recapitulates the patient cell phenotype, whereas no effects were observed in p.S143F LMNA keratinocytes, which highly express nesprin-2 giant. Overexpression of the mutant lamin A protein had a more severe impact on the NE of nesprin-2 giant deficient fibroblasts when compared with wild-type. In summary, our results suggest that the p.S143F lamin A mutation affects NE architecture and composition, chromatin organization, gene expression and transcription. Furthermore, our findings implicate a direct involvement of the nesprins in laminopathies and propose nesprin-2 giant as a structural reinforcer at the NE. © The Author 2007. Published by Oxford University Press. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.rightsHuman Molecular Genetics . Copyright © Oxford University Press.en_HK
dc.subject.meshAmino Acid Sequenceen_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshCells, Cultureden_HK
dc.subject.meshChromatin - metabolismen_HK
dc.subject.meshDNA Primers - geneticsen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshFibroblasts - metabolism - pathologyen_HK
dc.subject.meshGene Deletionen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLamin Type A - chemistry - genetics - metabolismen_HK
dc.subject.meshMembrane Proteins - deficiency - geneticsen_HK
dc.subject.meshMetalloendopeptidases - deficiency - geneticsen_HK
dc.subject.meshMicrofilament Proteins - deficiency - genetics - metabolismen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshNerve Tissue Proteins - deficiency - genetics - metabolismen_HK
dc.subject.meshNuclear Envelope - metabolism - pathologyen_HK
dc.subject.meshNuclear Proteins - deficiency - genetics - metabolismen_HK
dc.subject.meshPhenotypeen_HK
dc.subject.meshPoint Mutationen_HK
dc.subject.meshProgeria - genetics - metabolism - pathologyen_HK
dc.subject.meshSequence Homology, Amino Aciden_HK
dc.subject.meshTranscription, Geneticen_HK
dc.titleNesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=16&spage=2944&epage=59&date=2007&atitle=Nesprin-2+giant+safeguards+nuclear+envelope+architecture+in+LMNA+S143F+progeria+cellsen_HK
dc.identifier.emailZhou, Z:zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/hmg/ddm255en_HK
dc.identifier.pmid17881656-
dc.identifier.scopuseid_2-s2.0-35748967561en_HK
dc.identifier.hkuros140619en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-35748967561&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue23en_HK
dc.identifier.spage2944en_HK
dc.identifier.epage2959en_HK
dc.identifier.isiWOS:000251036400015-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridKandert, S=8293749000en_HK
dc.identifier.scopusauthoridLüke, Y=23473643200en_HK
dc.identifier.scopusauthoridKleinhenz, T=22953829600en_HK
dc.identifier.scopusauthoridNeumann, S=22953992400en_HK
dc.identifier.scopusauthoridLu, W=8601905700en_HK
dc.identifier.scopusauthoridJaeger, VM=22953325700en_HK
dc.identifier.scopusauthoridMunck, M=6601997059en_HK
dc.identifier.scopusauthoridWehnert, M=7007066678en_HK
dc.identifier.scopusauthoridMüller, CR=7404110456en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.scopusauthoridNoegel, AA=7006121369en_HK
dc.identifier.scopusauthoridDabauvalle, MC=6701430046en_HK
dc.identifier.scopusauthoridKarakesisoglou, I=6506717277en_HK

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