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

doi:10.1242/jcs.184150

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 journal › Article › peer-review

26 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 language	English (US)
Pages (from-to)	2732-2743
Number of pages	12
Journal	Journal of cell science
Volume	129
Issue number	14
DOIs	https://doi.org/10.1242/jcs.184150
State	Published - Jul 15 2016

Funding

This study was supported by the Sigrid Jusélius Foundation (Sigrid Juséliuksen Sää tiö) (to P.T.); the Finnish Medical Foundation (Suomen Lääketieteen Sää tiö) (to P.T.); the Academy of Finland (Suomen Akatemia) [grant number 290160 (to P.T.)]; the Finnish Foundation for Cardiovascular Research (Sydä ntutkimussää tiö) (to P.T.); Paavo Nurmi Foundation (to P.T.); Medicinska Understödsfö reningen Liv och Hä 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.

Keywords

Dilated cardiomyopathy
ER stress
Lamin
Laminopathy
UPR

ASJC Scopus subject areas

Cell Biology

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10.1242/jcs.184150

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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

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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",

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month = jul,

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doi = "10.1242/jcs.184150",

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West, G, Gullmets, J, Virtanen, L, Li, SP, Keinänen, A, Shimi, T, Mauermann, M, Heliö, T, Kaartinen, M, Ollila, L, Kuusisto, J, Eriksson, JE, Goldman, RD, 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, vol. 129, no. 14, pp. 2732-2743. https://doi.org/10.1242/jcs.184150

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T1 - Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

AU - West, Gun

AU - Gullmets, Josef

AU - Virtanen, Laura

AU - Li, Song Ping

AU - Keinänen, Anni

AU - Shimi, Takeshi

AU - Mauermann, Monika

AU - Heliö, Tiina

AU - Kaartinen, Maija

AU - Ollila, Laura

AU - Kuusisto, Johanna

AU - Eriksson, John E.

AU - Goldman, Robert D.

AU - Herrmann, Harald

AU - Taimen, Pekka

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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.

AB - 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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KW - ER stress

KW - Lamin

KW - Laminopathy

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JO - Journal of cell science

JF - Journal of cell science

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ER -

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

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