%0 Journal Article
%A West, Gun
%A Gullmets, Josef
%A Virtanen, Laura
%A Li, Song-Ping
%A Keinänen, Anni
%A Shimi, Takeshi
%A Mauermann, Monika
%A Heliö, Tiina
%A Kaartinen, Maija
%A Ollila, Laura
%A Kuusisto, Johanna
%A Eriksson, John E
%A Goldman, Robert D
%A Herrmann, Harald
%A Taimen, Pekka
%T Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy.
%J Journal of cell science
%V 129
%N 14
%@ 1477-9137
%C Cambridge
%I Company of Biologists Limited
%M DKFZ-2017-05941
%P 2732 - 2743
%D 2016
%X 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.
%K Biomarkers (NLM Chemicals)
%K Lamin Type A (NLM Chemicals)
%K Mutant Proteins (NLM Chemicals)
%K Protein Aggregates (NLM Chemicals)
%K lamin C (NLM Chemicals)
%K Green Fluorescent Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:27235420
%2 pmc:PMC4958296
%R 10.1242/jcs.184150
%U https://inrepo02.dkfz.de/record/130863