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.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
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 Pdoi
10.1242/jcs.184150subject
Has Abstractpub_date
2016-07-15 00:00:00pages
2732-43issue
14eissn
0021-9533issn
1477-9137pii
jcs.184150journal_volume
129pub_type
杂志文章abstract：:Cell migration is essential for normal development and many pathological processes. Rho-family small GTPases play important roles in this event. In particular, Rac regulates lamellipodia formation at the leading edge during migration. The small GTPase RhoG activates Rac through its effector ELMO and the ELMO-binding p...
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doi：
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