Journal Article

DKFZ-2017-05941

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy.

West, G. ; Gullmets, J. ; Virtanen, L. ; Li, S.-P. ; Keinänen, A. ; Shimi, T. ; Mauermann, M.DKFZ* ; Heliö, T. ; Kaartinen, M. ; Ollila, L. ; Kuusisto, J. ; Eriksson, J. E. ; Goldman, R. D. ; Herrmann, H.DKFZ* ; Taimen, P.

2016
Company of Biologists Limited Cambridge

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Please use a persistent id in citations: doi:10.1242/jcs.184150

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.

Keyword(s): Biomarkers ; Lamin Type A ; Mutant Proteins ; Protein Aggregates ; lamin C ; Green Fluorescent Proteins

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. Molekulare Genetik (B060)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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