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  • 1
    Online Resource
    Online Resource
    A lamin A/C variant causing striated muscle disease provides insights into filament organization
    The Company of Biologists ; 2021
    In:  Journal of Cell Science Vol. 134, No. 6 ( 2021-03-15)
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 134, No. 6 ( 2021-03-15)
    Abstract: The LMNA gene encodes the A-type lamins, which polymerize into ∼3.5-nm-thick filaments and, together with B-type lamins and associated proteins, form the nuclear lamina. Mutations in LMNA cause a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from LmnaH222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filaments in situ and using a nuclear extraction protocol. Averaging of individual segments of filaments in LmnaH222P/H222P mouse fibroblasts resolved two polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.
    Type of Medium: Online Resource
    ISSN: 0021-9533 , 1477-9137
    URL: Article
    DOI: 10.1242/jcs.256156
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2021
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy
    The Company of Biologists ; 2001
    In:  Journal of Cell Science Vol. 114, No. 24 ( 2001-12-15), p. 4435-4445
    Details
    In: Journal of Cell Science, The Company of Biologists, Vol. 114, No. 24 ( 2001-12-15), p. 4435-4445
    Abstract: Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene, which encodes lamin A and lamin C. Mutations in this gene also give rise to limb girdle muscular dystrophy type 1B, dilated cardiomyopathy with atrioventricular conduction defect and Dunnigan-type partial lipodystrophy. The properties of the mutant lamins that cause muscular dystrophy, lipodystrophy and dilated cardiomyopathy are not known. We transfected C2C12 myoblasts with cDNA encoding wild-type lamin A and 15 mutant forms found in patients affected by these diseases. Immunofluorescence microscopy showed that four mutants, N195K, E358K, M371K and R386K, could have a dramatically aberrant localization, with decreased nuclear rim staining and formation of intranuclear foci. The distributions of endogenous lamin A/C, lamin B1 and lamin B2 were also altered in cells expressing these four mutants and three of them caused a loss of emerin from the nuclear envelope. In the yeast two-hybrid assay, the 15 lamin A mutants studied interacted with themselves and with wild-type lamin A and lamin B1. Pulse-chase experiments showed no decrease in the stability of several representative lamin A mutants compared with wild-type. These results indicate that some lamin A mutants causing disease can be aberrantly localized, partially disrupt the endogenous lamina and alter emerin localization, whereas others localize normally in transfected cells.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.114.24.4435
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2001
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
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  • 3
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    Online Resource
    Muscle dystrophy-causing ΔK32 lamin A/C mutant does not impair functions of nucleoplasmic LAP2α - lamin A/C complexes in mice
    The Company of Biologists ; 2013
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: A-type lamins are components of the nuclear lamina, a filamentous network of the nuclear envelope in metazoans that supports nuclear architecture. In addition, lamin A/C can also be found in the nuclear interior. This nucleoplasmic lamin pool is soluble in physiological buffer, depends on the presence of the lamin-binding protein, Lamina-associated polypeptide 2α (LAP2α) and regulates cell cycle progression in tissue progenitor cells. ΔK32 mutations in A-type lamins cause severe congenital muscle disease in humans and a muscle maturation defect in LmnaΔK32/ΔK32 knock-in mice. At molecular level, mutant ΔK32 lamin A/C protein levels were reduced and all mutant lamin A/C was soluble and mislocalized to the nucleoplasm. To test the role of LAP2α in nucleoplasmic ΔK32 lamin A/C regulation and functions, we deleted LAP2α in LmnaΔK32/ΔK32 knock-in mice. In double mutant mice the LmnaΔK32/ΔK32- linked muscle defect was unaffected. LAP2α interacted with mutant lamin A/C, but unlike wild-type lamin A/C, the intranuclear localization of ΔK32 lamin A/C was not affected by loss of LAP2α. In contrast, loss of LAP2α in LmnaΔK32/ΔK32 mice impaired the regulation of tissue progenitor cells like in lamin A/C wild type animals. These data indicate that a LAP2α-independent assembly defect of ΔK32 lamin A/C is predominant for the mouse pathology, while the LAP2α-linked functions of nucleoplasmic lamin A/C in the regulation of tissue progenitor cells are not affected in LmnaΔK32/ΔK32 mice.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.115246
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2013
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
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  • 4
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    Online Resource
    FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation
    The Company of Biologists ; 2014
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: FHL1 mutations cause several clinically heterogeneous myopathies including Reducing Body Myopathy (RBM), Scapuloperoneal Myopathy (SPM) and X-Linked Myopathy with Postural Muscle Atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates designated “Reducing Bodies” (RBs) containing mutant FHL1 are detected in RBM muscle but not several other FHL1 myopathies. Here RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1 and formed aggregates positive for the RB stain Menadione-NBT, analogous to RBM muscle aggregates. However HCM and EDMD FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation however RBM, SPM and XMPMA mutations impaired differentiation, consistent with loss-of-normal function. Furthermore, SPM and XMPMA mutants retarded myotube formation relative to vector control consistent with a dominant-negative/toxic function. Mutant FHL1 myotube formation was partially rescued by expression of the FHL1-binding partner constitutively-active NFATc1. This is the first study to show FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impaired myotube formation suggesting a common pathogenic mechanism despite heterogenous clinical features.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.140905
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2014
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors
    The Company of Biologists ; 2014
    In:  Journal of Cell Science
    Details
    In: Journal of Cell Science, The Company of Biologists
    Abstract: The mechanisms underlying cell response to mechanical forces are critical for muscle development and functionality. We aim to determine whether mutations of the LMNA gene causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts (LMNA) embedded in soft matrix did not align along the gel axis whereas control myoblasts did. LMNA myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft 2D and/or static 3D conditions, LMNA myoblasts demonstrated enhanced activation of Yes-Associated Protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. SiRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in lamin A/C mutated myoblasts.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    URL: Article
    DOI: 10.1242/jcs.144907
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2014
    detail.hit.zdb_id: 219171-4
    detail.hit.zdb_id: 1483099-1
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
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