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

  • Gun West (Contributor)
  • Josef Gullmets (Contributor)
  • Laura Virtanen (Contributor)
  • Takeshi Shimi (Contributor)
  • Monika Mauermann (Contributor)
  • Maija Kaartinen (Contributor)
  • Laura Ollila (Contributor)
  • Johanna Kuusisto (Contributor)
  • Harald Herrmann (Contributor)
  • Pekka Taimen (Contributor)



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 is 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 mutant lamin expressing cells further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability. Total RNA obtained from 4 control and 7 patient cell lines
Date made available2016

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