Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

Journal article


Publication Details

Author(s): West G, Gullmets J, Virtanen L, Li SP, Keinanen A, Shimi T, Mauermann M, Helio T, Kaartinen M, Ollila L, Kuusisto J, Eriksson JE, Goldman RD, Herrmann H, Taimen P
Journal: Journal of Cell Science
Publication year: 2016
Volume: 129
Journal issue: 14
Pages range: 2732-43
ISSN: 0021-9533


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.



External institutions with authors

Åbo Akademi University
Deutsches Krebsforschungszentrum (DKFZ)
Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS)
Northwestern University
University of Eastern Finland
University of Turku / Turun yliopisto


How to cite

APA:
West, G., Gullmets, J., Virtanen, L., Li, S.-P., Keinanen, A., Shimi, T.,... Taimen, P. (2016). Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy. Journal of Cell Science, 129(14), 2732-43. https://dx.doi.org/10.1242/jcs.184150

MLA:
West, Gun, et al. "Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy." Journal of Cell Science 129.14 (2016): 2732-43.

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Last updated on 2018-07-10 at 03:08