title: Increased plasticity of the nuclear envelope and hypermobility of telomeres due to the loss of A-type lamins.
abstract: BACKGROUND
  The nuclear lamina provides structural support to the nucleus and has a central role in defining nuclear organization. Defects in its filamentous constituents, the lamins, lead to a class of diseases collectively referred to as laminopathies. On the cellular level, lamin mutations affect the physical integrity of nuclei and nucleo-cytoskeletal interactions, resulting in increased susceptibility to mechanical stress and altered gene expression.
  
  
  METHODS
  In this study we quantitatively compared nuclear deformation and chromatin mobility in fibroblasts from a homozygous nonsense LMNA mutation patient and a Hutchinson-Gilford progeria syndrome patient with wild type dermal fibroblasts, based on the visualization of mCitrine labeled telomere-binding protein TRF2 with light-economical imaging techniques and cytometric analyses.
  
  
  RESULTS
  Without application of external forces, we found that the absence of functional lamin A/C leads to increased nuclear plasticity on the hour and minute time scale but also to increased intranuclear mobility down to the second time scale. In contrast, progeria cells show overall reduced nuclear dynamics. Experimental manipulation (farnesyltransferase inhibition or lamin A/C silencing) confirmed that these changes in mobility are caused by abnormal or reduced lamin A/C expression.
  
  
  CONCLUSIONS
  These observations demonstrate that A-type lamins affect both nuclear membrane and telomere dynamics.
  
  
  CONCLUSIONS
  Because of the pivotal role of dynamics in nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.
authors.affiliation: Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium. winnok.devos@Ugent.be
authors.forename: Winnok H
authors.initials: WH
authors.lastname: De Vos
authors.forename: Frederik
authors.initials: F
authors.lastname: Houben
authors.forename: Ron A
authors.initials: RA
authors.lastname: Hoebe
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Baziel
authors.initials: B
authors.lastname: van Engelen
authors.forename: Erik M M
authors.initials: EM
authors.lastname: Manders
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Jos L V
authors.initials: JL
authors.lastname: Broers
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Oostveldt
mesh_terms: D002460:Cell Line; D048430:Cell Shape; D018389:Codon, Nonsense; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics*; D009685:Nuclear Envelope / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D012867:Skin / Q000166:cytology; D012879:Skin Physiological Phenomena
chemical_list: D018389:Codon, Nonsense; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C440308:lamin C; C090764:prelamin A