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

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 (2016)


Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 129

Pages Range: 2732-43

Journal Issue: 14

DOI: 10.1242/jcs.184150

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.

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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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