Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene

Vigouroux, Corinne; Auclair, Martine; Dubosclard, Emmanuelle; Pouchelet, M.; Capeau, Jacqueline; Courvalin, Jean-Claude; Buendia, Brigitte

doi:10.1242/jcs.114.24.4459

Cited by 220 publications

(24 citation statements)

References 52 publications

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“…Different combinations of nuclear abnormalities are characteristic of different cancer types, and nuclear appearances are often used for cancer diagnosis and staging. Similar alterations in nuclear morphology are seen in cells lacking specific NE proteins or expressing mutant NE proteins, suggesting a possible link between dysregulated NE proteins and cancer pathology [37,210,211].…”

Section: Altered Nuclear Structure and Morphology In Cancer Cellsmentioning

confidence: 79%

The Role of Emerin in Cancer Progression and Metastasis

Liddane

Holaska

2021

IJMS

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It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due to its incredibly large size. Nuclear structural changes are predicted to regulate cancer cell migration. Nuclear abnormalities are common across a vast spectrum of cancer types, regardless of tissue source, mutational spectrum, and signaling dependencies. The pervasiveness of nuclear alterations suggests that changes in nuclear structure may be crucially linked to the transformation process. The factors driving these nuclear abnormalities, and the functional consequences, are not completely understood. Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamina proteins, including emerin, is found in many cancers and this expression is correlated with better clinical outcomes. A model is emerging whereby emerin, as well as other nuclear lamina proteins, binding to the nucleoskeleton regulates the nuclear structure to impact metastasis. In this model, emerin and lamins play a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Herein, we discuss the cellular functions of nuclear lamina proteins, with a particular focus on emerin, and how these functions impact cancer progression and metastasis.

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Section: Altered Nuclear Structure and Morphology In Cancer Cellsmentioning

confidence: 79%

The Role of Emerin in Cancer Progression and Metastasis

Liddane

Holaska

2021

IJMS

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“…The role of lamins in the pathophysiology of these tissue specific diseases is intriguing since A-type lamins are expressed in almost all differentiated somatic cells. We recently analyzed the nuclear structure of fibroblasts from patients with FPLD and observed abnormally decondensed chromatin areas juxtaposed with disorganized lamina networks (7), suggesting that an alteration of lamina-chromatin interactions may play a role in the pathophysiology of the disease.…”

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confidence: 99%

The Carboxyl-Terminal Region Common to Lamins A and C Contains a DNA Binding Domain

et al. 2003

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Lamins A and C are intermediate filament proteins which polymerize into the nucleus to form the nuclear lamina network. The lamina is apposed to the inner nuclear membrane and functions in tethering chromatin to the nuclear envelope and in maintaining nuclear shape. We have recently characterized a globular domain that adopts an immunoglobulin fold in the carboxyl-terminal tail common to lamins A and C. Using an electrophoretic mobility shift assay (EMSA), we show that a peptide containing this domain interacts in vitro with DNA after dimerization through a disulfide bond, but does not interact with the core particle or the dinucleosome. The covalent dimer binds a 30-40 bp DNA fragment with a micromolar affinity and no sequence specificity. Using nuclear magnetic resonance (NMR) and an EMSA, we observed that two peptide regions participate in the DNA binding: the unstructured amino-terminal part containing the nuclear localization signal and a large positively charged region centered around amino acid R482 at the surface of the immunoglobulin-like domain. Mutations R482Q and -W, which are responsible for Dunnigan-type partial lipodystrophy, lower the affinity of the peptide for DNA. We conclude that the carboxyl-terminal end of lamins A and C binds DNA and suggest that alterations in lamin-DNA interactions may play a role in the pathophysiology of some lamin-linked diseases.

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“…Successively, lamin expression and distribution were evaluated in vitro on HDFs carrying two novel LMNA variants: R189Q and E317K. Moreover, nuclear abnormalities and irregularities in lamin staining were assessed in order to correlate them to variant nature and disease phenotype [ 45 , 46 , 47 , 48 , 49 ]. The increased percentage of abnormal nuclei, irrespective of the type of nuclear malformation, is the most discriminating parameter between normal and lamin-defective cells [ 50 ], correlating with nuclear architecture instability [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants

Ferradini

Cosma

Romeo

et al. 2021

JCM

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Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype–phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.

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Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene

Cited by 220 publications

References 52 publications

The Role of Emerin in Cancer Progression and Metastasis

The Role of Emerin in Cancer Progression and Metastasis

The Carboxyl-Terminal Region Common to Lamins A and C Contains a DNA Binding Domain

Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants

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