scholarly journals Severe Mandibuloacral Dysplasia-Associated Lipodystrophy and Progeria in a Young Girl with a Novel Homozygous Arg527Cys LMNA Mutation

2008 ◽  
Vol 93 (12) ◽  
pp. 4617-4623 ◽  
Author(s):  
Anil K. Agarwal ◽  
Irina Kazachkova ◽  
Svetlana Ten ◽  
Abhimanyu Garg
Keyword(s):  
Joint Stiffness ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Prelamin A ◽  
Farnesyl Transferase ◽  
Mandibular Hypoplasia ◽  
Lmna Mutation ◽  
Geranylgeranyl Transferase ◽  
Mandibuloacral Dysplasia

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24). Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy. Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts. Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase. Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

scholarly journals Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2383
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Metastasis ◽  
Metastatic Cancer ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Soft Agar ◽  
Lamin A ◽  
And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells

2011 ◽  
Vol 39 (6) ◽  
pp. 1698-1704 ◽  
Author(s):  
Giovanna Lattanzi
Keyword(s):  
Nuclear Envelope ◽  
Accelerated Aging ◽  
Nuclear Lamina ◽  
Major Constituent ◽  
Lamin A ◽  
Post Translational Modifications ◽  
Prelamin A ◽  
Chromatin Dynamics ◽  
Chromatin Arrangement ◽  
And Function

Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor.

scholarly journals Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model.

2019 ◽  
Vol 5 (3) ◽  
pp. eaav5078 ◽  
Author(s):  
Ying Ao ◽  
Jie Zhang ◽  
Zuojun Liu ◽  
Minxian Qian ◽  
Yao Li ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Lamin A ◽  
Catalytic Core ◽  
Prelamin A ◽  
Damage Repair ◽  
Nuclear Lamin ◽  
Activity Loss ◽  
Ck2 Kinase

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A inLmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates inZmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.

scholarly journals Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina.

1992 ◽  
Vol 89 (7) ◽  
pp. 3000-3004 ◽  
Author(s):  
R. J. Lutz ◽  
M. A. Trujillo ◽  
K. S. Denham ◽  
L. Wenger ◽  
M. Sinensky
Keyword(s):  
Nuclear Lamina ◽  
Lamin A ◽  
Prelamin A

scholarly journals Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

2021 ◽  
Author(s):  
Clare Rogerson ◽  
Duncan J. Wotherspoon ◽  
Cristina Tommasi ◽  
Robert W. Button ◽  
Ryan F. L. O’Shaughnessy
Keyword(s):  
Actin Filament ◽  
Molecular Mechanisms ◽  
Molecular Motor ◽  
Nuclear Lamina ◽  
Nuclear Volume ◽  
Volume Reduction ◽  
Epidermal Keratinocytes ◽  
Lamin A ◽  
Myosin Iia

AbstractKeratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures. Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 min precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1-associated proteins prevented nuclear volume reduction. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction.

scholarly journals Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

2009 ◽  
Vol 94 (12) ◽  
pp. 4971-4983 ◽  
Author(s):  
Abhimanyu Garg ◽  
Lalitha Subramanyam ◽  
Anil K. Agarwal ◽  
Vinaya Simha ◽  
Benjamin Levine ◽  
...  
Keyword(s):  
Clinical Features ◽  
Trichostatin A ◽  
Epifluorescence Microscopy ◽  
Lamin A ◽  
Metabolic Complications ◽  
Prelamin A ◽  
Progeroid Syndrome ◽  
Number Of Patients ◽  
Hands And Feet ◽  
Mandibuloacral Dysplasia

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.

scholarly journals Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

2021 ◽  
Vol 4 (10) ◽  
pp. e202101120
Author(s):  
Ching-Tung Chu ◽  
Yi-Hsuan Chen ◽  
Wen-Tai Chiu ◽  
Hong-Chen Chen
Keyword(s):  
Tyrosine Phosphorylation ◽  
Genomic Instability ◽  
Posttranslational Modifications ◽  
Nuclear Lamina ◽  
Serine Phosphorylation ◽  
Lamin A ◽  
Intact Cells ◽  
Structure And Activity

Lamins form the nuclear lamina, which is important for nuclear structure and activity. Although posttranslational modifications, in particular serine phosphorylation, have been shown to be important for structural properties and functions of lamins, little is known about the role of tyrosine phosphorylation in this regard. In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells. The phosphomimetic Y45D mutant was diffusively distributed in the nucleoplasm and failed to assemble into the nuclear lamina. Depletion of lamin A/C in HeLa cells induced nuclear dysmorphia and genomic instability as well as increased nuclear plasticity for cell migration, all of which were partially restored by re-expression of lamin A, but further promoted by the Y45D mutant. Together, our results reveal a novel mechanism for regulating the assembly of nuclear lamina through Src and suggest that aberrant phosphorylation of lamin A by Src may contribute to nuclear dysmorphia, genomic instability, and nuclear plasticity.

scholarly journals Lamin B constitutes an intermediate filament attachment site at the nuclear envelope.

1987 ◽  
Vol 105 (1) ◽  
pp. 117-125 ◽  
Author(s):  
S D Georgatos ◽  
G Blobel
Keyword(s):  
Plasma Membrane ◽  
Specific Binding ◽  
Attachment Site ◽  
Nuclear Lamina ◽  
Membrane Skeleton ◽  
Eukaryotic Cells ◽  
Lamin A ◽  
Lamin B ◽  
Nuclear Lamins

We found that urea extraction of turkey erythrocyte nuclear envelopes abolished their ability to bind exogenous 125I-vimentin, while, at the same time, it removed the nuclear lamins from the membranes. After purification of the lamins from such urea extracts, a specific binding between isolated vimentin and lamin B, or a lamin A + B hetero-oligomer, was detected by affinity chromatography. Similar analysis revealed that the 6.6-kD vimentin tail piece was involved in this interaction. By other approaches (quantitative immunoprecipitation, rate zonal sedimentation, turbidometric assays) a substoichiometric lamin B-vimentin binding was determined under in vitro conditions. It was also observed that anti-lamin B antibodies but not other sera (anti-lamin A, anti-ankyrin, preimmune) were able to block 70% of the binding of 125I-vimentin to native, vimentin-depleted, nuclear envelopes. These data, which were confirmed by using rat liver nuclear lamins, indicate that intermediate filaments may be anchored directly to the nuclear lamina, providing a continuous network connecting the plasma membrane skeleton with the karyoskeleton of eukaryotic cells.

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