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

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: 13.22). 08/2009; 119(7):1825-36. DOI: 10.1172/JCI37679
Source: PubMed


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.

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    • "Laminopathies represent a wide group of genetically determined disorders with variable clinical phenotypes arising from mutations in the LMNA gene [1] [2] [3]. More than ten clinical entities linked to lamin A/ C mutations have presently been described, including skeletal muscle disorders (Emery–Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, congenital muscle dystrophy), cardiac muscle disorders (dilated cardiomyopathy, cardiac conduction disease, heart-hand syndrome ), disorders of adipose tissue (familial partial lipodystrophy — FPLD, lipoatrophy, mandibuloacral dystrophy — MAD), neurological disorders (Charcot–Marie–Tooth disease), skin disorders (restrictive dermopathy, acrogeria), and a group of premature aging disorders (Hutchinson–Gilford progeria syndrome and atypical Werner syndrome ) [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. "
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    ABSTRACT: Various mutations in LMNA gene, encoding for nuclear lamin A/C protein, lead to laminopathies and contribute to over ten human disorders, mostly affecting tissues of mesenchymal origin such as fat tissue, muscle tissue, and bones. Recently it was demonstrated that lamins not only play a structural role providing communication between extra-nuclear structures and components of cell nucleus but also control cell fate and differentiation. In our study we assessed the effect of various LMNA mutations on the expression profile of mesenchymal multipotent stem cells (MMSC) during adipogenic and osteogenic differentiation. We used lentiviral approach to modify human MMSC with LMNA-constructs bearing mutations associated with different laminopathies - G465D, R482L, G232E, R527C, and R471C. The impact of various mutations on MMSC differentiation properties and expression profile was assessed by colony-forming unit analysis, histological staining, expression of the key differentiation markers promoting adipogenesis and osteogenesis followed by the analysis of the whole set of genes involved in lineage-specific differentiation using PCR expression arrays. We demonstrate that various LMNA mutations influence the differentiation efficacy of MMSC in mutation-specific manner. Each LMNA mutation promotes a unique expression pattern of genes involved in a lineage-specific differentiation and this pattern is shared by the phenotype-specific mutations. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Molecular Genetics and Metabolism
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    • "It is known that rescue of abnormal nuclear morphology in HGPS fibroblasts can be achieved by FTI treatment, which reduces the amount of the persistently farnesylated progerin form of lamin A [Capell et al., 2005; Glynn and Glover, 2005; Mallampalli et al., 2005; Toth et al., 2005]. At the organismal level, a decrease in farnesylated lamin A isoforms is also associated with an improvement in overall phenotypes in progeroid mice and humans [Denecke et al., 2006; Worman et al., 2009; Yang et al., 2010]. It is notable that despite proficient prelamin A processing in LCPS patient fibroblasts (Fig. 3C), we find a significant improvement in the nuclear morphology of LCPS cells upon FTI treatment (Fig. 3D). "
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    ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2013 · American Journal of Medical Genetics Part A
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    • "While the classical EDMD phenotype was first attributed to EMD and LMNA mutations, it is now apparent that the same mutations in these genes can cause dilated cardiomyopathy with more variable skeletal muscle involvement [6,9,15-21]. Intriguingly, LMNA mutations (different than those leading to myopathy) can also cause partial lipodystrophy, peripheral neuropathy, or accelerated aging disorders such as Hutchinson-Gilford progeria syndrome [22]. "
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    ABSTRACT: Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, more variable skeletal muscle can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology. Sections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength. We detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing. Our results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy.
    Full-text · Article · Jul 2013 · Skeletal Muscle
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