TY  - JOUR
AU  - West, Gun
AU  - Gullmets, Josef
AU  - Virtanen, Laura
AU  - Li, Song-Ping
AU  - Keinänen, Anni
AU  - Shimi, Takeshi
AU  - Mauermann, Monika
AU  - Heliö, Tiina
AU  - Kaartinen, Maija
AU  - Ollila, Laura
AU  - Kuusisto, Johanna
AU  - Eriksson, John E
AU  - Goldman, Robert D
AU  - Herrmann, Harald
AU  - Taimen, Pekka
TI  - Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy.
JO  - Journal of cell science
VL  - 129
IS  - 14
SN  - 1477-9137
CY  - Cambridge
PB  - Company of Biologists Limited
M1  - DKFZ-2017-05941
SP  - 2732 - 2743
PY  - 2016
AB  - 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.
KW  - Biomarkers (NLM Chemicals)
KW  - Lamin Type A (NLM Chemicals)
KW  - Mutant Proteins (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - lamin C (NLM Chemicals)
KW  - Green Fluorescent Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27235420
C2  - pmc:PMC4958296
DO  - DOI:10.1242/jcs.184150
UR  - https://inrepo02.dkfz.de/record/130863
ER  -