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@ARTICLE{West:130863,
author = {G. West and J. Gullmets and L. Virtanen and S.-P. Li and A.
Keinänen and T. Shimi and M. Mauermann$^*$ and T. Heliö
and M. Kaartinen and L. Ollila and J. Kuusisto and J. E.
Eriksson and R. D. Goldman and H. Herrmann$^*$ and P.
Taimen},
title = {{D}eleterious assembly of the lamin {A}/{C} mutant
p.{S}143{P} causes {ER} stress in familial dilated
cardiomyopathy.},
journal = {Journal of cell science},
volume = {129},
number = {14},
issn = {1477-9137},
address = {Cambridge},
publisher = {Company of Biologists Limited},
reportid = {DKFZ-2017-05941},
pages = {2732 - 2743},
year = {2016},
abstract = {Mutation of the LMNA gene, encoding nuclear lamin A and
lamin C (hereafter lamin A/C), is a common cause of familial
dilated cardiomyopathy (DCM). Among Finnish DCM patients,
the founder mutation c.427T>C (p.S143P) is the most
frequently reported genetic variant. Here, we show that
p.S143P lamin A/C is more nucleoplasmic and soluble than
wild-type lamin A/C and accumulates into large intranuclear
aggregates in a fraction of cultured patient fibroblasts as
well as in cells ectopically expressing either FLAG- or
GFP-tagged p.S143P lamin A. In fluorescence loss in
photobleaching (FLIP) experiments, non-aggregated
EGFP-tagged p.S143P lamin A was significantly more dynamic.
In in vitro association studies, p.S143P lamin A failed to
form appropriate filament structures but instead assembled
into disorganized aggregates similar to those observed in
patient cell nuclei. A whole-genome expression analysis
revealed an elevated unfolded protein response (UPR) in
cells expressing p.S143P lamin A/C. Additional endoplasmic
reticulum (ER) stress induced by tunicamycin reduced the
viability of cells expressing mutant lamin further. In
summary, p.S143P lamin A/C affects normal lamina structure
and influences the cellular stress response, homeostasis and
viability.},
keywords = {Biomarkers (NLM Chemicals) / Lamin Type A (NLM Chemicals) /
Mutant Proteins (NLM Chemicals) / Protein Aggregates (NLM
Chemicals) / lamin C (NLM Chemicals) / Green Fluorescent
Proteins (NLM Chemicals)},
cin = {B062 / B060},
ddc = {570},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)B060-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:27235420},
pmc = {pmc:PMC4958296},
doi = {10.1242/jcs.184150},
url = {https://inrepo02.dkfz.de/record/130863},
}