Consequences of Lmna Exon 4 Mutations in Myoblast Function

Gómez-Domínguez, Déborah; Epifano, Carolina; Miguel, Fernando de; Castaño, Albert G.; Vilaplana-Martí, Borja; Martín, A.; Amarilla-Quintana, Sandra; Bertrand, Anne T.; Bonne, Gisèle; Ramón‐Azcón, Javier; Rodríguez-Milla, Miguel Ángel; Castro, Ignacio Pérez de

doi:10.20944/preprints202004.0232.v1

Cited by 3 publications

(1 citation statement)

References 34 publications

(35 reference statements)

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“…Finally, proteolytic removal of the farnesylated C-terminus end by a specific endoprotease (ZMPSTE24) leads to mature lamin A [ 11 ]. Lamin A/C has been demonstrated to play a key role during myoblast differentiation [ 12 , 13 , 14 ]. In particular, lamin A/C association with the regulatory regions of muscle genes is able to influence muscle differentiation [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Santi

Cenni

Capanni

et al. 2020

Cells

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Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamina A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.

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Section: Introductionmentioning

confidence: 99%

PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Santi

Cenni

Capanni

et al. 2020

Cells

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Tuning between Nuclear Organization and Functionality in Health and Disease

Manda

Golla

Sesham

et al. 2023

Cells

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The organization of eukaryotic genome in the nucleus, a double-membraned organelle separated from the cytoplasm, is highly complex and dynamic. The functional architecture of the nucleus is confined by the layers of internal and cytoplasmic elements, including chromatin organization, nuclear envelope associated proteome and transport, nuclear–cytoskeletal contacts, and the mechano-regulatory signaling cascades. The size and morphology of the nucleus could impose a significant impact on nuclear mechanics, chromatin organization, gene expression, cell functionality and disease development. The maintenance of nuclear organization during genetic or physical perturbation is crucial for the viability and lifespan of the cell. Abnormal nuclear envelope morphologies, such as invagination and blebbing, have functional implications in several human disorders, including cancer, accelerated aging, thyroid disorders, and different types of neuro-muscular diseases. Despite the evident interplay between nuclear structure and nuclear function, our knowledge about the underlying molecular mechanisms for regulation of nuclear morphology and cell functionality during health and illness is rather poor. This review highlights the essential nuclear, cellular, and extracellular components that govern the organization of nuclei and functional consequences associated with nuclear morphometric aberrations. Finally, we discuss the recent developments with diagnostic and therapeutic implications targeting nuclear morphology in health and disease.

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Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome

Wilke,

Wick,

Schwab

et al. 2024

Genes

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The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.

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Consequences of Lmna Exon 4 Mutations in Myoblast Function

Cited by 3 publications

References 34 publications

PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Tuning between Nuclear Organization and Functionality in Health and Disease

Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome

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