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

Gun West, Josef Gullmets, Laura Virtanen, Song Ping Li, Anni Keinänen, Takeshi Shimi, Monika Mauermann, Tiina Heliö, Maija Kaartinen, Laura Ollila, Johanna Kuusisto, John E. Eriksson, Robert D. Goldman, Harald Herrmann, Pekka Taimen*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2732-2743
Number of pages12
JournalJournal of cell science
Volume129
Issue number14
DOIs
StatePublished - Jul 15 2016

Keywords

  • Dilated cardiomyopathy
  • ER stress
  • Lamin
  • Laminopathy
  • UPR

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy'. Together they form a unique fingerprint.

  • Cite this

    West, G., Gullmets, J., Virtanen, L., Li, S. P., Keinänen, A., Shimi, T., Mauermann, M., Heliö, T., Kaartinen, M., Ollila, L., Kuusisto, J., Eriksson, J. E., Goldman, R. D., Herrmann, H., & 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), 2732-2743. https://doi.org/10.1242/jcs.184150