Nuclear Envelope, Nuclear Lamina, and Inherited Disease

Worman, Howard J.; Courvalin, Jean-Claude

doi:10.1016/s0074-7696(05)46006-4

Cited by 102 publications

(83 citation statements)

References 294 publications

(329 reference statements)

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“…[2] LBR resides in the inner nuclear membrane of the interphase nucleus, possessing a highly positively charged N-terminus (~200 amino acid residues, believed to interact with lamin B, HP1 and chromatin) and a C-terminus (~400 amino acid residues, with 8 putative transmembrane segments and sterol reductase activity). [34] At present, the mechanism by which LBR controls granulocyte nuclear shape and heterochromatin distribution remains largely speculative. [2,24] Even so, the necessity for sufficient amounts of LBR is well documented from analysis of single gene mutations in human Pelger-Huët anomaly (PHA) [3] and murine Ichthyosis (ic).…”

Section: Discussionmentioning

confidence: 99%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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Objective-Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Huët anomaly (PHA) and mouse ichthyosis (ic). In this study we have utilized differentiated promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression.Materials and Methods-Wildtype (+/+), heterozygous (+/ic) and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation.Results-Wildtype (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells.Conclusions-Our observations suggest roles for LBR during granulopoiesis which may involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin and promoting down-regulation of lamin A/C expression. Category Granulopoiesis

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Section: Discussionmentioning

confidence: 99%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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“…Nuclear lobulation in primary fibroblasts is associated with several human lamin A disease mutations (6) and is found in C. elegans embryos down-regulated for Ce-lamin (26). Therefore, it was interesting that nuclear lobulation was observed for some mutations in a stage-and tissue-specific manner.…”

Section: Abnormal Filament Assembly In Vitro Can Help Explain Severalmentioning

confidence: 99%

Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

Wiesel

Mattout

Melcer

et al. 2008

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

138

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Lamins are nuclear intermediate filament proteins and the major building blocks of the nuclear lamina. Besides providing nuclear shape and mechanical stability, lamins are required for chromatin organization, transcription regulation, DNA replication, nuclear assembly, nuclear positioning, and apoptosis. Mutations in human lamins cause many different heritable diseases, affecting various tissues and causing early aging. Although many of these mutations result in nuclear deformation, their effects on lamin filament assembly are unknown. Caenorhabditis elegans has a single evolutionarily conserved lamin protein, which can form stable 10-nmthick filaments in vitro. To gain insight into the molecular basis of lamin filament assembly and the effects of laminopathic mutations on this process, we investigated mutations in conserved residues of the rod and tail domains that are known to cause various laminopathies in human. We show that 8 of 14 mutant lamins present WT-like assembly into filaments or paracrystals, whereas 6 mutants show assembly defects. Correspondingly, expressing these mutants in transgenic animals shows abnormal distribution of Ce-lamin, abnormal nuclear shape or change in lamin mobility. These findings help in understanding the role of individual residues and domains in laminopathy pathology and, eventually, promote the development of therapeutic interventions. filament assembly ͉ laminopathic diseases ͉ nuclear envelope

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“…Mutations in the human lamin A/C (LMNA) gene cause 16 different diseases with considerable clinical variability, ranging from cardiac and skeletal myopathies to lipodystrophy, peripheral neuropathy, and premature aging(4), (5). Despite this clinical heterogeneity some LMNA mutations cause particular phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Wolf

Wang

Alcalai

et al. 2008

Journal of Molecular and Cellular Cardiology

147

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Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna +/-mice. Despite one normal allele, Lmna +/-mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna +/-mice but by 4 weeks of age AV nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10 week-old Lmna +/-mice showed atrioventricular (AV) conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month old Lmna +/-mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna +/-mice revealed DCM; in some mice this occurred without Contact address: Charles I. Berul, M.D., Department of Cardiology -Children's Hospital, 300 Longwood Ave., Boston, MA 02115 USA, Phone: 617 355-6432, Fax: 617 566-5671, charles.berul@cardio.chboston.org. * These authors contributed equally to this publication. Disclosures: NonePublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript J Mol Cell Cardiol. Author manuscript; available in PMC 2010 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.

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Nuclear Envelope, Nuclear Lamina, and Inherited Disease

Cited by 102 publications

References 294 publications

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

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