Increased plasticity of the nuclear envelope and hypermobility of telomeres due to the loss of A-type lamins.
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.
De Vos
Winnok H
WH
Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium. winnok.devos@Ugent.be
Houben
Frederik
F
Hoebe
Ron A
RA
Hennekam
Raoul
R
van Engelen
Baziel
B
Manders
Erik M M
EM
Ramaekers
Frans C S
FC
Broers
Jos L V
JL
Van Oostveldt
Patrick
P
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
D018389:Codon, Nonsense; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C440308:lamin C; C090764:prelamin A