The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

Al-Saaidi, Rasha Abdelkadhem; Rasmussen, Torsten Bloch; Palmfeldt, Johan; Nissen, Peter H.; Beqqali, Abdelaziz; Hansen, Jakob; Pinto, Yigal M.; Boesen, Thomas; Bross, Peter

doi:10.1016/j.yexcr.2013.08.024

Cited by 23 publications

(29 citation statements)

References 26 publications

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“…Since exogenously expressed lamin can undergo autophagy-related proteolysis in HEK 293 cells (Cenni et al 2011), and proteolytic degradation may be induced among other mechanisms by Akt1 phosphorylation of lamin A on serine 404 (Cenni et al 2008; Bertacchini et al 2013), it is plausible that autophagy-related proteolysis may be a possible mechanism. Similar feature of unpredicted level of expression was observed in the cause of lamin A nonsense mutant (pArg321Ter) causing dilated cardiomyopathy (Al-Saaidi et al 2013). …”

Section: Discussionsupporting

confidence: 63%

The effect of the lamin A and its mutants on nuclear structure, cell proliferation, protein stability, and mobility in embryonic cells

et al. 2016

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LMNA gene encodes for nuclear intermediate filament proteins lamin A/C. Mutations in this gene lead to a spectrum of genetic disorders, collectively referred to as laminopathies. Lamin A/C are widely expressed in most differentiated somatic cells but not in early embryos and some undifferentiated cells. To investigate the role of lamin A/C in cell phenotype maintenance and differentiation, which could be a determinant of the pathogenesis of laminopathies, we examined the role played by exogenous lamin A and its mutants in differentiated cell lines (HeLa, NHDF) and less-differentiated HEK 293 cells. We introduced exogenous wild-type and mutated (H222P, L263P, E358K D446V, and ∆50) lamin A into different cell types and analyzed proteins’ impact on proliferation, protein mobility, and endogenous nuclear envelope protein distribution. The mutants give rise to a broad spectrum of nuclear phenotypes and relocate lamin C. The mutations ∆50 and D446V enhance proliferation in comparison to wild-type lamin A and control cells, but no changes in exogenous protein mobility measured by FRAP were observed. Interestingly, although transcripts for lamins A and C are at similar level in HEK 293 cells, only lamin C protein is detected in western blots. Also, exogenous lamin A and its mutants, when expressed in HEK 293 cells underwent posttranscriptional processing. Overall, our results provide new insight into the maintenance of lamin A in less-differentiated cells. Embryonic cells are very sensitive to lamin A imbalance, and its upregulation disturbs lamin C, which may influence gene expression and many regulatory pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00412-016-0610-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 63%

The effect of the lamin A and its mutants on nuclear structure, cell proliferation, protein stability, and mobility in embryonic cells

et al. 2016

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“…In a recent study from our group, we showed that in dilated cardiomyopathy patients heterozygous for a premature stop codon in LMNA, the mutant transcript is degraded by the nonsense mediated mRNA decay (NMD) leading to haploinsufficiency of lamin A and lamin C. Surprisingly, lamin A protein and not lamin C from the wt allele was also reduced in patient fibroblasts (Al-Saaidi et al 2013). This finding indicates that low lamin A concentration may make it more unstable and more susceptible to various influences.…”

Section: Altered Lamin a To Lamin C Expression Ratio In Diseasesmentioning

confidence: 91%

Do lamin A and lamin C have unique roles?

Al-Saaidi

Bross

2014

Chromosoma

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The A-type lamins, lamin A and lamin C, generated from a single gene, LMNA, are major structural components of the nuclear lamina. The two alternative splice products have mostly been studied together because they have been considered to be interchangeable. However, several lines of evidence indicate that in spite of being generated from the same gene and having high similarities in their primary sequences, the two isoforms are not equivalent in different biological aspects in both health and disease. The key question is whether they have both overlapping and unique functions and whether they are distinctly regulated. Based on the so far available experimental evidence, lamin A appears to be the most regulated A-type isoform during development, aging, and disease which indicates that lamin A is implicated in many different biological aspects and may have a greater repertoire of specialized functions than lamin C. The aim of this review is to point out differences between the two major LMNA splice variants and the consequences of these differences on their functions. This may guide further research and be of prime importance for the understanding of the pathogenesis of LMNA mutations.

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“…Cardiac laminopathies result primarily from missense mutations (often in a dominant negative fashion), whilst truncating mutations resulting in Premature Termination Codon (PTC) are less common [6,7]. In order to better exploring the functional effects of LMNA truncating alterations associated to a cardiac phenotype, we recently studied a PTC mutation (R321X) upstream the LMNA Nuclear Localization Sequence (NLS) associated to severe cardiomyopathy [8].…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

Gerbino¹,

Bottillo²,

Milano³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Truncating LMNA gene mutations occur in many inherited cardiomyopathy cases, but the molecular mechanisms involved in the disease they cause have not yet been systematically investigated. Here, we studied a novel frameshift LMNA variant (p.D243Gfs*4) identified in three members of an Italian family co-segregating with a severe form of cardiomyopathy with conduction defects. Methods: HEK293 cells and HL-1 cardiomyocytes were transiently transfected with either Lamin A or D243Gfs*4 tagged with GFP (or mCherry). D243Gfs*4 expression, cellular localization and its effects on diverse cellular mechanisms were evaluated with western blotting, laser-scanning confocal microscopy and video-imaging analysis in single cells. Results: When expressed in HEK293 cells, GFP-(or mCherry)-tagged LMNA D243Gfs*4 colocalized with calnexin within the ER. ER mislocalization of LMNA D243Gfs*4 did not significantly induce ER stress response, abnormal Ca 2+ handling and apoptosis when compared with HEK293 cells expressing another truncated mutant of LMNA (R321X) which similarly accumulates within the ER. Of note, HEK293-LMNA D243Gfs*4 cells showed a significant reduction of connexin 43 (CX43) expression level, which was completely rescued by activation of the WNT/β-catenin signaling pathway. When expressed in HL-1 cardiomyocytes, D243Gfs*4 significantly impaired the spontaneous Ca 2+ oscillations recorded in these cells as result of propagation of the depolarizing waves through the gap junctions between non-

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The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

Cited by 23 publications

References 26 publications

The effect of the lamin A and its mutants on nuclear structure, cell proliferation, protein stability, and mobility in embryonic cells

The effect of the lamin A and its mutants on nuclear structure, cell proliferation, protein stability, and mobility in embryonic cells

Do lamin A and lamin C have unique roles?

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

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