Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects

Verga, Laura; Concardi, Monica; Pilotto, Andrea; Bellini, O; Pasotti, Michele; Repetto, Alessandra; Tavazzi, Luigi; Arbustini, Eloisa

doi:10.1007/s00428-003-0865-4

Cited by 46 publications

(41 citation statements)

References 30 publications

(28 reference statements)

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“…The first two observations are likely due to specific interactions with transcriptional regulators, but the alterations in chromatin are likely due to epigenetic misregulation. Specifically dense chromatin that is normally directly apposed to the NE redistributes away from the membrane in patients with lamin-related muscular dystrophy [122,123], progeria [124] and INM protein-related NE diseases such as emerin-linked muscular dystrophy [125][126][127]. Similar alterations in chromatin organization were observed in mouse lamin depletion models [128] and transgenic mice expressing lamin point mutants associated with cardiomyopathy [129].…”

Section: Ne Diseases and Epigeneticssupporting

confidence: 53%

The epigenetics of nuclear envelope organization and disease

Schirmer

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Mammalian chromosomes and some specific genes have non-random positions within the nucleus that are tissue-specific and heritable. Work in many organisms has shown that genes at the nuclear periphery tend to be inactive and altering their partitioning to the interior results in their activation. Proteins of the nuclear envelope can recruit chromatin with specific epigenetic marks and can also recruit silencing factors that add new epigenetic modifications to chromatin sequestered at the periphery. Together these findings indicate that the nuclear envelope is a significant epigenetic regulator. The importance of this function is emphasized by observations of aberrant distribution of peripheral heterochromatin in several human diseases linked to mutations in NE proteins. These debilitating inherited diseases range from muscular dystrophies to the premature aging progeroid syndromes and the heterochromatin changes are just one early clue for understanding the molecular details of how they work. The architecture of the nuclear envelope provides a unique environment for epigenetic regulation and as such a great deal of research will be required before we can ascertain the full range of its contributions to epigenetics.

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Section: Ne Diseases and Epigeneticssupporting

confidence: 53%

The epigenetics of nuclear envelope organization and disease

Schirmer

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…These types of changes are observed in cardiomyocytes where lamin A͞C gene is abnormal (40,41). Nuclear lamins give the nucleus its shape and are involved in chromatin organization, DNA replication, gene expression, and transmission of mechanical signals from the cell surface to the nucleus (42)(43)(44)(45)(46). We found in the present study that although there was no reduction in the cellular content of lamin A͞C, there was loss of lamin A͞C from the nuclear envelope in ER␤ Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the ERβ ^– /–mouse heart

Förster

Kietz

Hultenby

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Although the heart responds to estrogen, it is not clear whether estrogen acts directly on heart muscle or indirectly by means of the vascular, immune, or nervous system. No role for estrogen receptor (ER) β in the heart has been established, but ERβ –/– mice are hypertensive, and as they age, their hearts become enlarged. Histological and ultrastructural analysis of the heart revealed a disarray of myocytes, a disruption of intercalated discs, an increase in the number and size of gap junctions, and a profound alteration in nuclear structure, concomitantly with a loss of expression of lamin A/C from the nuclear envelope. In the lungs of ERβ –/– mice, lamin A/C was located in the nuclear membrane, indicating that lamin A/C is not an ERβ-regulated gene. Immunohistochemical studies with ERβ antibodies failed to detect ERβ in the myocardium. We conclude that abnormalities in heart morphology in ERβ –/– mice are likely due to stress on the nuclear envelope as a result of the chronic sustained systolic and diastolic hypertension observed in ERβ –/– mice. Because neither ERα nor ERβ could be detected in heart muscle, the effects of estrogen on the myocardium seem to be indirect.

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“…The convoluted shapes of the nuclei, blebs, discontinuous layer of heterochromatin, and possible enlarged nuclear pores are features commonly seen in other LMNA mutations. 23,24,39 It should be kept in mind that such structural defects can also be found in DCM patients without LMNA mutations. 40 Apart from their function in nuclear stability, it has been suggested that lamin proteins are important for the structural integrity of the whole cell through interactions between nuclear lamina, the cytoskeleton, and the extracellular matrix.…”

Section: Hoorntje Et Al Mild Phenotype In Lmna P(arg331gln) Carriersmentioning

confidence: 99%

Lamin A/C -Related Cardiac Disease

Hoorntje¹,

Bollen²,

Barge-Schaapveld³

et al. 2017

Circ Cardiovasc Genet

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T he LMNA gene encodes for the intermediate filament proteins lamin A and C. LMNA mutations are associated with a wide spectrum of phenotypes ranging from progeroid syndromes, muscular disease, and lipodystrophy to isolated cardiac disease (dilated cardiomyopathy [DCM] and conduction disorders) and phenotypes consisting of combinations of these different features.1 Although their precise role is unknown, LMNA proteins are believed to play an important role in the structural integrity of the cell nucleus and in gene regulation. 2LMNA is one of the genes most frequently involved in genotyped DCM.3 Sinus node dysfunction, atrioventricular conduction disorders, and supraventricular and ventricular arrhythmias often precede or accompany DCM.4 LMNArelated cardiac disease is associated with a high incidence of major cardiac events like sudden cardiac death, appropriate implantable cardioverter-defibrillator (ICD) therapy, or endstage heart failure. DCM patients with an LMNA mutation are, in general, believed to have a poor prognosis compared with non-LMNA mutation DCM patients. 5,6 Currently, with all the new DNA-sequencing technologies implemented in routine patient care, increasing numbers Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membranepermeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p. (Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations b...

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Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects

Cited by 46 publications

References 30 publications

The epigenetics of nuclear envelope organization and disease

The epigenetics of nuclear envelope organization and disease

Characterization of the ERβ ^– /–mouse heart

Lamin A/C -Related Cardiac Disease

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Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects

Cited by 46 publications

References 30 publications

The epigenetics of nuclear envelope organization and disease

The epigenetics of nuclear envelope organization and disease

Characterization of the ERβ – /–mouse heart

Lamin A/C -Related Cardiac Disease

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Characterization of the ERβ ^– /–mouse heart