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

J Cell Sci. 2016 Jul 15;129(14):2732-43. doi: 10.1242/jcs.184150. Epub 2016 May 27.

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.

Keywords: Dilated cardiomyopathy; ER stress; Lamin; Laminopathy; UPR.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / metabolism
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / pathology*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / ultrastructure
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Lamin Type A / metabolism*
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Protein Aggregates
  • Transfection
  • Up-Regulation

Substances

  • Biomarkers
  • Lamin Type A
  • Mutant Proteins
  • Protein Aggregates
  • lamin C
  • Green Fluorescent Proteins

Supplementary concepts

  • Familial dilated cardiomyopathy