Laminopathies and the long strange trip from basic cell biology to therapy.

Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
The Journal of clinical investigation (Impact Factor: 15.39). 08/2009; 119(7):1825-36. DOI: 10.1172/JCI37679
Source: PubMed

ABSTRACT The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases ("laminopathies"), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.

  • 06/2014; 2(2):1-112. DOI:10.4199/C00107ED1V01Y201406BBC007
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    ABSTRACT: The lamins are nuclear envelope proteins and main constituent of nuclear lamina surrounding the internal membrane of nuclear envelope. The lamina is the scaffold for nuclear envelope architecture and a framework composed of intermediate filament proteins such as type A and B lamins. Type A lamins (lamin A/C) are encoded by LMNA gene and are at the center of several biological functions essential for cells. Several studies have shown that mutations in LMNA gene are responsible for laminophathies associated with abnormalities in skeletal muscle, in heart, in adipose tissue, bone tissue and neuronal tissue. Lamin A and lamin C are synthesized from the differential splicing of the same messenger RNA but they have different type of maturations. The mutations in LMNA gene affect more often the maturation of lamin A and most of the physiological pathologies are linked to the absence of functional lamin A. Lamin A is a biomarker of differentiated cells and its synthesis is stimulated by vitamin A in embryonic stem cells. The suppressions of lamin A in vivo by endogen épigénétique modifications or in vitro by the interference RNA (iRNA) techniques or enzymatic degradations, reveal the central role of lamin A in the regulation of genes involved in cell division, DNA replication, DNA repair, gene transcription, chromatin organization, cell metabolism, sensitivity to insulin, cell motility, cell signaling, and cell immunity. Epithelial cell that had lost the capacity to express functional lamin A are frequently transformed in cancerous cells while adipose cells that had lost functional lamin A also lack the capacity to metabolize lipids and become resistant to insulin. In this review we emphasize the molecular mechanism involved in cancer genesis, in insulin-resistance and diabetes when the expression of lamin A is altered or lost as well as methods to restore lamins A/C expression.
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    Genetic Disorders, Edited by Maria Puiu, 01/2013: chapter 2: pages 27-64; Intech., ISBN: 978-953-51-0886-3


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