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.
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland.
authors.forename: Gun
authors.initials: G
authors.lastname: West
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Josef
authors.initials: J
authors.lastname: Gullmets
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Virtanen
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland.
authors.forename: Song-Ping
authors.initials: SP
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Keinänen
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimi
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany Institute of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Mauermann
authors.affiliation: Heart and Lung Center Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Heliö
authors.affiliation: Heart and Lung Center Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Kaartinen
authors.affiliation: Heart and Lung Center Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Ollila
authors.affiliation: Department of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany Institute of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland MediCity Research Laboratory, 20520 Turku, Finland pekka.taimen@utu.fi.
authors.forename: Pekka
authors.identifier: 0000-0001-8849-4604
authors.initials: P
authors.lastname: Taimen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D066329:Protein Aggregates; D014162:Transfection; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D034904:Lamin Type A; D050505:Mutant Proteins; D066329:Protein Aggregates; C440308:lamin C; D049452:Green Fluorescent Proteins
keywords: Dilated cardiomyopathy; ER stress; Lamin; Laminopathy; UPR