@article{97ecc8eac7c6424daf30d560a7d5d45f,
title = "Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy",
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",
author = "Gun West and Josef Gullmets and Laura Virtanen and Li, {Song Ping} and Anni Kein{\"a}nen and Takeshi Shimi and Monika Mauermann and Tiina Heli{\"o} and Maija Kaartinen and Laura Ollila and Johanna Kuusisto and Eriksson, {John E.} and Goldman, {Robert D.} and Harald Herrmann and Pekka Taimen",
note = "Funding Information: This study was supported by the Sigrid Jus{\'e}lius Foundation (Sigrid Jus{\'e}liuksen S{\"a}{\"a} ti{\"o}) (to P.T.); the Finnish Medical Foundation (Suomen L{\"a}{\"a}ketieteen S{\"a}{\"a} ti{\"o}) (to P.T.); the Academy of Finland (Suomen Akatemia) [grant number 290160 (to P.T.)]; the Finnish Foundation for Cardiovascular Research (Syd{\"a} ntutkimuss{\"a}{\"a} ti{\"o}) (to P.T.); Paavo Nurmi Foundation (to P.T.); Medicinska Underst{\"o}dsf{\"o} reningen Liv och H{\"a} lsa r.f. (to G.W.); Svenska Kulturfonden (to J.G.); the Hospital District of Southwest Finland, Turku University Hospital ERVA funds (to P.T.); the Progeria Research Foundation (to R.D.G); the National Institutes of Health-National Institute of General Medical Sciences (to R.D.G.); and the German Research Foundation (Deutsche Forschungsgemeinschaft) [grant number HE 1853, to H.H.]. Deposited in PMC for release after 12 months. Publisher Copyright: {\textcopyright} 2016. Published by The Company of Biologists Ltd.",
year = "2016",
month = jul,
day = "15",
doi = "10.1242/jcs.184150",
language = "English (US)",
volume = "129",
pages = "2732--2743",
journal = "The Quarterly journal of microscopical science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "14",
}