Affinage

LMNA

Prelamin-A/C · UniProt P02545

Round 2 corrected
Length
664 aa
Mass
74.1 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LMNA encodes the nuclear intermediate filament proteins lamin A and lamin C, generated by alternative splicing, which polymerize to form the nuclear lamina and serve as a central integrator of nuclear architecture, chromatin organization, mechanotransduction, gene regulation, and DNA integrity. Lamin A/C maintains nuclear envelope integrity, anchors lamina-associated chromatin domains (LADs) that suppress transcription ~16-fold relative to non-LAD regions, interacts with HDAC2 to modulate histone acetylation during DNA damage responses, physically inhibits c-Myc transactivation, and transmits cytoskeletal forces through LINC complexes containing Nesprin-1 (PMID:38577741, PMID:30109767, PMID:38769668, PMID:35925868). Lamin-A protein levels scale with tissue stiffness and direct mesenchymal stem cell lineage specification through a retinoic acid receptor feedback loop (PMID:23990565). Dominantly acting LMNA mutations cause a spectrum of diseases—dilated cardiomyopathy with conduction defects, Emery-Dreifuss muscular dystrophy, and Hutchinson-Gilford progeria syndrome—through mechanisms including aberrant lamin self-assembly and lamin B1 sequestration, hyperactivation of ERK1/2–cofilin–MRTF-A/SRF and AKT–mTOR–autophagy cascades, PDGF pathway dysregulation, connexin-43 mislocalization, loss of peripheral heterochromatin, and—in HGPS—production of the permanently farnesylated progerin via a cryptic exon 11 splice site whose usage is governed by RNA secondary structure and SR proteins SRSF1/SRSF2 (PMID:10580070, PMID:10080180, PMID:12714972, PMID:28844980, PMID:23048029, PMID:31316208, PMID:36550158, PMID:21875900).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1986 High

    Determining the primary structure of lamins A and C established that LMNA products belong to the intermediate filament family and share an α-helical rod domain, resolving the molecular identity of the nuclear lamina scaffold.

    Evidence cDNA cloning and deduced amino acid sequence comparison by two independent groups

    PMID:3453101 PMID:3462705

    Open questions at the time
    • No in vivo functional analysis of individual lamin domains
    • Mechanism of lamin polymer assembly not yet resolved
    • Regulation of lamin A vs. C expression unknown
  2. 1999 High

    Identification of LMNA mutations as the cause of both autosomal dominant Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy with conduction disease revealed that a structural nuclear envelope protein could cause tissue-specific disease, launching the laminopathy field.

    Evidence Candidate gene sequencing with co-segregation analysis in multiple families for both EDMD and DCM

    PMID:10080180 PMID:10580070

    Open questions at the time
    • Mechanism by which nuclear lamina defects cause striated muscle-selective pathology unknown
    • No animal models yet available
    • No explanation for genotype-phenotype variability across mutations
  3. 2003 High

    Discovery that the HGPS G608G silent mutation activates a cryptic exon 11 splice site to produce progerin (lamin A Δ50) established aberrant pre-mRNA splicing as the molecular basis of progeria and identified progerin as a dominant-negative truncated lamin.

    Evidence Genetic mapping and LMNA sequencing in 20 HGPS cases by two independent groups; immunofluorescence showing nuclear envelope abnormalities

    PMID:12702809 PMID:12714972

    Open questions at the time
    • Mechanism by which 50-aa deletion causes dominant nuclear disruption unclear
    • No therapeutic strategy to block cryptic splice site
    • Whether progerin accumulates in normal aging unknown
  4. 2004 High

    Demonstrating that progerin causes progressive, concentration-dependent dominant-negative disruption of nuclear architecture—lobulation, lamina thickening, heterochromatin loss, nuclear pore clustering—by introducing it into normal cells established the cell-autonomous toxicity mechanism of HGPS.

    Evidence Electron and light microscopy of HGPS fibroblasts; transfection and protein injection of progerin into normal cells

    PMID:15184648

    Open questions at the time
    • Whether these architectural defects directly cause the clinical phenotype or act through downstream signaling
    • Reversibility of progerin-induced changes not tested
  5. 2005 High

    A knock-in mouse model of LMNA-N195K DCM showed that lamin A/C mutations cause misexpression and mislocalization of connexins 40/43 and disorganization of desmin at intercalated disks, providing the first mechanistic link between nuclear lamina defects and cardiac conduction abnormalities.

    Evidence Homologous recombination knock-in mouse; continuous ECG monitoring; immunofluorescence for connexins and desmin

    PMID:15972724

    Open questions at the time
    • Whether connexin mislocalization is a direct or indirect consequence of lamin mutation
    • Mechanism connecting nuclear defect to intercalated disk remodeling unknown
  6. 2006 High

    Detection of low-level progerin expression via the same cryptic splice site in normal aged human cells linked the LMNA locus to physiological aging, showing that age-dependent nuclear defects mirror HGPS pathology.

    Evidence RT-PCR for cryptic splice product in normal aged cells; immunofluorescence for nuclear defects; splice-site inhibition rescue

    PMID:16645051

    Open questions at the time
    • Quantitative contribution of progerin to normal aging versus other aging pathways unclear
    • No in vivo demonstration in aged human tissues beyond fibroblasts
  7. 2009 High

    The R439C mutation demonstrated that an introduced cysteine in lamin A enables disulfide-mediated oligomerization and enhanced DNA binding, revealing redox-sensitive structural perturbation as a disease mechanism.

    Evidence Gel retardation assays, ESR spectroscopy, and immunofluorescence in patient fibroblasts

    PMID:19220582

    Open questions at the time
    • Whether disulfide-mediated oligomerization occurs under physiological redox conditions in vivo
    • General relevance to other cysteine-introducing mutations untested
  8. 2010 High

    Multiple studies converged to show that LMNA mutations trigger apoptosis through both FAS and mitochondrial pathways, damage telomeres (rescued by telomerase), and that lymphocyte defects in Lmna−/− mice are cell-extrinsic, establishing that lamin A/C loss acts partly through non-cell-autonomous and stress-response mechanisms.

    Evidence Cardiac-specific LMNA-E82K transgenic mice with apoptosis pathway analysis; telomerase rescue of HGPS cells with γ-H2AX/telomere FISH; bone marrow and thymus transplantation in Lmna−/− mice

    PMID:20405040 PMID:20605919 PMID:21151901

    Open questions at the time
    • Whether telomere damage is the primary driver of HGPS senescence or a secondary effect
    • Identity of the cell-extrinsic factor causing lymphocyte defects in Lmna−/− mice unknown
    • Relative contributions of FAS vs mitochondrial apoptosis pathways in human DCM unclear
  9. 2011 High

    RNA structure analysis and SR protein perturbation showed that the HGPS mutation disrupts a conserved RNA secondary structure near the cryptic splice site, and that SRSF1/SRSF6 regulate the progerin:lamin A ratio in a dose-dependent manner controlling lifespan in mice, establishing splice regulation as a therapeutic target.

    Evidence RNA structure mapping; SRSF1/SRSF6 RNAi in HGPS-like mouse fibroblasts; survival analysis in heterozygous vs homozygous mice

    PMID:21875900

    Open questions at the time
    • Complete set of trans-acting splicing regulators not mapped
    • Whether pharmacological modulation of SR proteins is feasible in vivo
  10. 2012 High

    Identification of hyperactivated AKT-mTOR signaling (via ERK1/2-induced Dusp4) that impairs autophagy in Lmna-H222P hearts, with pharmacological mTOR inhibition rescuing cardiomyopathy, established a druggable signaling cascade downstream of LMNA mutations.

    Evidence Expression and pathway analysis in Lmna-H222P/H222P mouse hearts; Dusp4 cardiac-selective transgenics; mTOR pharmacological inhibition with cardiac function assessment

    PMID:23044536 PMID:23048029

    Open questions at the time
    • Whether mTOR inhibition is effective across different LMNA mutations
    • Long-term efficacy and safety of mTOR inhibition not assessed
    • Direct link between lamina disruption and ERK1/2 activation mechanism unknown
  11. 2013 High

    Proteomic and biophysical studies demonstrated that lamin-A protein levels scale with tissue stiffness, that lamin A directs stem cell lineage via a retinoic acid receptor feedback loop, and that lamin A interacts with matrin-3 through its C-terminal tail—interactions disrupted by myopathic mutations—integrating mechanosensing with nuclear organization.

    Evidence Multi-tissue proteomics; stem cell differentiation on variable-stiffness matrices; co-IP and 3D mapping of lamin A–matrin-3 interaction; BioID proximal proteome of lamin A

    PMID:22412018 PMID:23990565 PMID:25948554

    Open questions at the time
    • Signaling pathway connecting matrix stiffness to lamin A protein stability unresolved
    • Whether matrin-3 interaction mediates specific gene regulation
    • Full interactome of lamin A C-terminal tail incomplete
  12. 2016 High

    Antisense oligonucleotides targeting SRSF2 binding sites in exon 11 shifted splicing from lamin A/progerin toward lamin C in vivo, reducing progerin in HGPS fibroblasts and providing a proof-of-concept therapeutic splice-switching strategy.

    Evidence ASO transfection in mouse and human fibroblasts; SRSF2 knockdown; RT-PCR quantification; in vivo ASO administration in mice

    PMID:26999604

    Open questions at the time
    • Long-term in vivo efficacy and tissue-specific delivery of ASOs not demonstrated
    • Whether complete elimination of lamin A (shifting entirely to lamin C) would be tolerated
  13. 2017 High

    Biophysical analysis revealed that DCM-causing LMNA mutations increase lamin A self-association up to 10-fold and alter heterotypic interaction with lamin B1, sequestering it into nuclear aggregates, directly linking altered polymerization properties to lamina disorganization.

    Evidence Circular dichroism, fluorescence spectroscopy, isothermal titration calorimetry, confocal and super-resolution microscopy

    PMID:28844980

    Open questions at the time
    • Whether altered self-association kinetics occur in the assembled nuclear lamina in vivo
    • Structural basis at atomic resolution not determined
  14. 2019 High

    Two key mechanistic advances: PDGF pathway activation was identified as a driver of arrhythmia and calcium dysregulation in LMNA-mutant iPSC-cardiomyocytes (rescued by PDGFR-β inhibition), and SHAPE-MaP structural mapping defined the RNA structural determinants governing cryptic splice site selection in HGPS.

    Evidence Patient iPSC-CMs with isogenic controls, calcium imaging, pharmacological/siRNA rescue; SHAPE-MaP of LMNA pre-mRNA with systematic mutagenesis

    PMID:31006814 PMID:31316208

    Open questions at the time
    • Upstream mechanism connecting lamina disruption to PDGF pathway activation unknown
    • Whether PDGFR-β inhibition translates to clinical benefit
    • How RNA structure changes are sensed by the spliceosome in vivo
  15. 2021 High

    DamID profiling in iPSC-derived cardiomyocytes showed that LMNA mutations specifically disrupt peripheral chromatin anchoring at transcriptionally active, lamin B1-low regions enriched for non-cardiac lineage genes, revealing that the lamin A/C network safeguards cell-type identity by restraining alternative-lineage gene expression.

    Evidence DamID for lamina-chromatin contacts in iPSC-CMs, hepatocytes, and adipocytes with LMNA mutations; RNA-seq; patient myocardium validation

    PMID:33529599

    Open questions at the time
    • Whether restoring LAD anchoring is sufficient to rescue cardiomyocyte identity
    • Mechanism by which lamin A/C selectively tethers specific chromatin domains remains unclear
  16. 2022 High

    A detailed signaling cascade was delineated: ERK1/2 phosphorylates cofilin-1 (Thr25), which sequesters MRTF-A in the cytoplasm, reducing SRF-dependent ATAT1 transcription, lowering α-tubulin acetylation, and causing Cx43 mislocalization—a chain rescued by tubastatin A in Lmna-H222P mice—while separately, BAF-dependent recruitment of nucleoplasmic A-type lamins to nuclear rupture sites was shown to be blocked by progeria-associated mutations and farnesylation.

    Evidence Co-IP of phospho-cofilin-1/MRTF-A; Atat1 KO mice; patient iPSC-CMs; tubastatin A rescue; live-cell imaging of nuclear ruptures with BAF KO and farnesyltransferase inhibition

    PMID:35269487 PMID:36550158

    Open questions at the time
    • Whether MRTF-A sequestration contributes to pathology beyond connexin mislocalization
    • Whether BAF-dependent rupture repair is relevant in terminally differentiated cardiomyocytes in vivo
  17. 2023 High

    Genome-wide END-seq in LMNA-deficient cardiomyocytes revealed increased DNA double-strand breaks preferentially at gene bodies and cardiac TF motifs in non-LAD regions, while disruption of Nesprin-1 KASH domain suppressed Lmna-linked cardiac pathology by reducing microtubule-dependent nuclear forces, connecting mechanical stress transmission to genomic instability.

    Evidence END-seq and CUT&RUN in WT vs Myh6-Cre:LmnaF/F cardiac myocytes; CRISPR disruption of Nesprin-1 KASH domain in Lmna mutant mice with cardiac pathology assessment

    PMID:35925868 PMID:38577741

    Open questions at the time
    • Whether DSBs are a cause or consequence of cardiomyocyte dysfunction
    • Identity of the repair pathways most affected in LMNA-deficient cardiomyocytes
    • Whether Nesprin-1 KASH disruption is a viable therapeutic strategy

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions remain: the direct mechanism by which lamin A/C disruption activates ERK1/2 and PDGF signaling cascades; whether restoring chromatin-lamina contacts (LADs) is sufficient to rescue cellular identity; the atomic-resolution structure of lamin A/C polymers in situ; and whether splice-switching or LINC-complex-targeting therapies can achieve durable clinical benefit in laminopathies.
  • No direct signaling intermediary identified between lamina disruption and ERK1/2/PDGF activation
  • No high-resolution in situ structure of lamin A/C filaments
  • Clinical translation of splice-switching ASOs and mTOR/PDGFR-β inhibitors not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0003677 DNA binding 2 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005635 nuclear envelope 5 GO:0005694 chromosome 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 2 R-HSA-5357801 Programmed Cell Death 1
Partners
BANF1HDAC2LMNB1MATR3MYCSRSF1SRSF2SYNE1
Complex memberships
nuclear lamina

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 Lamin A and C share an alpha-helical rod domain with extensive homology to the intermediate filament protein family, establishing LMNA products as nuclear intermediate filaments; lamin A contains an extra 9.0-kDa carboxyl-terminal tail not present in lamin C. cDNA sequencing and deduced amino acid sequence comparison Proceedings of the National Academy of Sciences of the United States of America High 3453101 3462705
1999 Missense mutations in the rod domain of LMNA cause autosomal dominant dilated cardiomyopathy with conduction-system disease, while head/tail domain mutations cause Emery-Dreifuss muscular dystrophy, demonstrating domain-specific functional roles of the LMNA-encoded intermediate filament proteins in cardiac conduction and contractility. Exon sequencing of LMNA in 11 affected families, restriction-enzyme confirmation, segregation analysis The New England journal of medicine High 10080180 10580070
1999 Mutations in the LMNA gene (encoding lamins A and C produced by alternative splicing) cause autosomal dominant Emery-Dreifuss muscular dystrophy, establishing LMNA as the first nuclear lamina component implicated in inherited muscle disease. Chromosomal mapping to 1q11-q23, candidate gene sequencing identifying four mutations co-segregating with disease in five families Nature genetics High 10080180
2003 A recurrent de novo point mutation G608G (GGC>GGT) in exon 11 of LMNA activates a cryptic splice site, producing a lamin A protein lacking 50 amino acids near the carboxy terminus (progerin/LAΔ50) that causes Hutchinson-Gilford Progeria Syndrome; immunofluorescence showed visible nuclear membrane abnormalities in HGPS fibroblasts. Chromosomal mapping using uniparental isodisomy and interstitial deletion; LMNA sequencing in 20 classical HGPS cases; immunofluorescence with anti-lamin A antibodies Nature High 12702809 12714972
2004 Accumulation of the HGPS mutant lamin A (LAΔ50/progerin) causes progressive concentration-dependent dominant-negative changes in nuclear architecture including nuclear envelope lobulation, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores; introducing LAΔ50 into normal cells by transfection or protein injection induces the same defects. Light and electron microscopy of HGPS cells; transfection and protein injection of LAΔ50 into normal cells; progressive culture of HGPS cells Proceedings of the National Academy of Sciences of the United States of America High 15184648
2006 Normal healthy cells sporadic use of the same cryptic splice site in LMNA that is constitutively activated in HGPS; cell nuclei from old individuals accumulate progerin and acquire nuclear defects similar to HGPS cells including changes in histone modifications and increased DNA damage, implicating lamin A in physiological aging. RT-PCR detection of cryptic splice product in normal aged cells; immunofluorescence for nuclear defects; splice-site inhibition to reverse defects Science High 16645051
2003 Lamin A/C is produced by alternative splicing of LMNA: lamin A and lamin C are generated by differential splicing within exon 10, producing isoforms with distinct carboxy termini; at least 41 disease-causing mutations predominantly missense affect specific functional domains. Mutation analysis by PCR/SSCP/sequencing across 12 exons; summary of published mutation-phenotype data Human mutation High 11102973
2005 Expression of the LMNA-N195K variant in knock-in mice causes dilated cardiomyopathy with conduction system disease and death from arrhythmia; the transcription factor Hf1b/Sp4 and gap junction proteins connexin 40 and connexin 43 are misexpressed and/or mislocalized in mutant hearts, and desmin staining reveals loss of organization at sarcomeres and intercalated disks. Homologous recombination knock-in mouse model; continuous ECG monitoring; immunofluorescence and western blotting Human molecular genetics High 15972724
2010 The LMNA E82K mutation causes mislocalization of lamin A in the nucleus, loss of nuclear envelope integrity, swollen mitochondria, and activates both FAS and mitochondrial pathways of apoptosis (increased FAS expression, cytochrome c release, activation of caspase-8, -9, -3) in heart-tissue-specific transgenic mice. Heart-tissue-specific transgenic mouse model; echocardiography; TUNEL assay; western blotting for FAS, cytochrome c, caspases; electron microscopy PloS one High 21151901
2010 Progerin-induced DNA damage signaling in HGPS is localized to telomeres, associated with telomere aggregates and chromosomal aberrations; telomerase extends HGPS cellular lifespan by decreasing progerin-induced DNA damage signaling and p53/Rb pathway activation, requiring both catalytic and DNA-binding functions of telomerase. Telomerase introduction into HGPS cells; γ-H2AX foci localization by immunofluorescence; proliferation assays; telomere FISH Journal of cell science High 20605919
2011 The HGPS mutation (c.1824C>T) changes the accessibility of the 5' splice site in LMNA exon 11 by disrupting a conserved RNA secondary structure; SR proteins SRSF1 and SRSF6 regulate the balance between lamin A and progerin production; RNAi depletion of SRSF1 in HGPS-like mouse fibroblasts reduces progerin and corrects dysmorphic nuclear phenotype; the progerin/lamin A splicing ratio controls lifespan in a dose-dependent manner in mice. RNA structure analysis; RNAi knockdown of SRSF1/SRSF6; HGPS-like mouse model (c.1827C>T); immunofluorescence for nuclear morphology; survival analysis of hetero- vs homozygous mice Human molecular genetics High 21875900
2012 Dual specificity phosphatase 4 (Dusp4) is transcriptionally induced by ERK1/2 in hearts of Lmna(H222P/H222P) mice and mediates cardiomyopathy by positively regulating AKT-mTOR signaling, which impairs autophagy; cardiac-selective overexpression of Dusp4 in transgenic mice reproduces LMNA cardiomyopathy phenotype. Expression analysis in Lmna(H222P/H222P) mouse hearts; Dusp4 cardiac-selective transgenic mice; AKT-mTOR pathway analysis; autophagy assays; echocardiography The Journal of biological chemistry High 23048029
2012 AKT-mTOR signaling is hyperactivated in hearts of Lmna(H222P/H222P) mice and impairs fasting-induced autophagy; pharmacological inhibition of mTOR ameliorates cardiomyopathy and is correlated with enhanced autophagy. Lmna(H222P/H222P) mouse hearts; western blotting for AKT-mTOR pathway components; fasting-induced autophagic flux assays; pharmacological mTOR blockade with cardiac function assessment Autophagy High 23044536
2013 Nuclear lamin-A levels scale with tissue stiffness across tissues; matrix stiffness directly regulates lamin-A protein levels; lamin-A influences lineage determination of stem cells (low lamin-A enhances fat differentiation on soft matrix; high lamin-A enhances bone differentiation on stiff matrix); lamin-A transcription is regulated by the vitamin A/retinoic acid pathway and nuclear entry of retinoic acid receptors is modulated by lamin-A levels. Proteomics of multiple tissues; stem cell differentiation assays on matrices of varying stiffness; lamin-A knockdown/overexpression; retinoic acid receptor nuclear import assays Science High 23990565
2012 BioID proximity labeling using lamin-A as bait identifies multiple proteins that associate with or are proximate to lamin A at the nuclear envelope in vivo, including a new NE-associated protein SLAP75, establishing the in vivo nuclear envelope proximal proteome of lamin A. BioID (proximity-dependent biotin identification) with lamin-A fusion protein; affinity capture of biotinylated proteins; mass spectrometry identification The Journal of cell biology High 22412018
2013 Lamin A interacts with matrin-3 via the carboxy-terminal lamin A tail; the LMNA truncating mutation Δ303 (which lacks the matrin-3 binding domain) increases the distance between lamin A and matrin-3 by 3D mapping; myopathic LMNA mutations disrupt this interaction. Mass spectrometry of proteins associated with lamin A tail; co-immunoprecipitation with anti-matrin-3 antibodies; 3D mapping of lamin A-matrin-3 interface; domain mapping of matrin-3 binding site Human molecular genetics High 25948554
2014 Lamin C expression (produced by alternative polyadenylation of LMNA, mutually exclusive with lamin A/progerin) and lamin A/progerin expression have antagonistic effects on energy metabolism and lifespan: lamin-C-only mice live longer with decreased energy metabolism, while progerin-expressing mice show increased energy metabolism, lipodystrophy, and increased mitochondrial biogenesis in adipose tissue. Mouse models expressing only lamin C or only progerin; metabolic phenotyping; transcriptome analysis of adipose tissue; mitochondrial quantification EMBO reports High 24639560
2016 SRSF2 binds to exon 11 sequences of LMNA pre-mRNA and regulates alternative splicing favoring lamin A over lamin C; an antisense oligonucleotide (ASO) targeting exon 11 increases lamin C production at the expense of prelamin A by blocking SRSF2 binding sites; the same ASO reduces progerin expression in HGPS patient fibroblasts and reduces lamin A/progerin in vivo in mice. ASO transfection in mouse and human fibroblasts; SRSF2 knockdown in cells and murine tissues; RT-PCR quantification of splice isoforms; in vivo ASO administration in mice The Journal of clinical investigation High 26999604
2017 DCM-associated LMNA mutations cause increased self-association (up to ten-fold higher association constant) of mutant lamin A compared to wild type; mutant lamin A shows differential heterotypic interaction with lamin B1, sequestering endogenous LB1 into nuclear aggregates, with significant secondary and tertiary structural alterations and altered stoichiometry/affinity. Circular dichroism; fluorescence spectroscopy; isothermal titration calorimetry (ITC); confocal and super-resolution (NSIM) microscopy in transfected cell lines Biochimica et biophysica acta. General subjects High 28844980
2009 The LMNA R439C mutation introduces an extra cysteine that forms disulfide-mediated lamin A/C oligomers, increases binding efficiency of the C-terminal domain to DNA (gel retardation assays), and causes increased ROS sensitivity in patient fibroblasts upon oxidative stress induction (ESR spectroscopy). Patient fibroblast analysis; gel retardation assays; electron spin resonance spectroscopy; immunofluorescence for honeycomb lamin formations Journal of cellular and molecular medicine High 19220582
2010 Lamin A interacts with HDAC2 in a dynamic complex that includes histone substrates; this interaction is reduced at the onset of DNA damage response and recovered after DNA repair completion; LMNA mutations causing progeroid phenotypes disrupt this lamin A/C-HDAC2 interplay and cause accumulation of p21 (CDKN1A) upon stress recovery. Co-immunoprecipitation of lamin A/C with HDAC2 in control and HGPS fibroblasts; oxidative stress induction; western blotting for p21; global histone acetylation analysis Aging cell High 30109767
2019 LMNA mutation-related DCM is mechanistically linked to activation of the PDGF signaling pathway in mutant iPSC-derived cardiomyocytes; pharmacological and molecular inhibition of PDGF signaling ameliorates arrhythmic phenotypes including aberrant calcium homeostasis. Patient-specific iPSC-derived cardiomyocytes with isogenic controls; electrophysiological studies; calcium imaging; transcriptomics; pharmacological and siRNA inhibition of PDGFR-β Nature High 31316208
2021 Pathogenic LMNA mutations in iPSC-derived cardiomyocytes (but not hepatocytes or adipocytes) cause specific disruptions in peripheral chromatin at regions enriched for transcriptionally active genes with lower lamin B1 contact frequency; disrupted regions are enriched for non-myocyte lineage genes and correlate with higher expression of those genes, revealing that the LMNA lamina network safeguards cardiac cellular identity. hiPSC differentiation into cardiomyocytes, hepatocytes, adipocytes with LMNA mutations; DamID for lamina-chromatin interactions; RNA-seq; patient myocardium analysis Cell stem cell High 33529599
2022 In cardiomyopathy-causing LMNA mutations, ERK1/2-phosphorylated cofilin-1 (on threonine 25) binds MRTF-A in the cytoplasm, preventing SRF stimulation in the nucleus; this reduces ATAT1 expression and α-tubulin acetylation; decreased tubulin acetylation causes Connexin 43 mislocalization; restoring α-tubulin acetylation with tubastatin A rescues Cx43 localization and cardiac function in Lmna(H222P/H222P) mice. Co-immunoprecipitation of phospho-cofilin-1 and MRTF-A; Atat1 knockout mice; iPSC-derived cardiomyocytes from LMNA mutation patients; tubastatin A treatment in Lmna(H222P/H222P) mice; cardiac function assessment Nature communications High 36550158
2023 Nesprin-1 LINC complexes are the predominant nuclear envelope anchor for microtubule cytoskeleton components (including nucleation activities and motor complexes) in mouse cardiomyocytes; disrupting the Nesprin-1 KASH domain suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. CRISPR disruption of Nesprin-1 KASH domain in mice; assessment of microtubule components at nucleus; nuclear morphology and positioning; cardiac pathology assessment in Lmna mutant mice Human molecular genetics High 35925868
2022 Progeria-associated LMNA mutations inhibit recruitment of affected A-type lamins to nuclear rupture sites; recruitment of mobile nucleoplasmic A-type lamins to ruptures is BAF-dependent via BAF's association with the Ig-like β-fold domain of A-type lamins; farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures unless farnesylation is inhibited. Live-cell imaging of nuclear ruptures; LMNA mutant constructs; BAF knockdown/knockout; farnesyltransferase inhibitor treatment; FRAP; domain mapping Cells High 35269487
2020 Activation of sarcolipin (an inhibitor of SERCA) is elevated early in LMNA cardiomyopathy in ventricular cardiomyocytes of Lmna mutant mice before left ventricular dysfunction is apparent; AAV9-mediated RNAi downregulation of sarcolipin delays cardiac dysfunction, demonstrating sarcolipin-mediated calcium handling dysregulation as a mechanism in LMNA cardiomyopathy. Lmna mutant mice; western blotting for sarcolipin; calcium handling assays; AAV9-RNAi in vivo delivery; echocardiography Biochemistry and biophysics reports High 32490213
2023 LMNA-deficient cardiac myocytes have increased DNA double-stranded breaks (DSBs) genome-wide (2.2% vs 0.8% prevalence); DSBs are preferentially localized to gene regions, transcription initiation sites, and cardiac transcription factor motifs; lamin-associated domains (LADs) are defined in cardiac myocytes by CUT&RUN, and constitutive LADs suppress transcript levels ~16-fold compared to non-LAD regions; DSBs are more common in non-LAD and loss-of-LAD regions. END-Sequencing of ~1 million cardiac myocytes per heart (WT vs Myh6-Cre:LmnaF/F); CUT&RUN for LAD identification in cardiac myocytes; RNA-seq integration Cardiovascular research High 38577741
2013 In LMNA R527H (MADA) patient fibroblasts, the lamin A precursor protein accumulation causes impaired DNA damage repair after X-ray exposure (increased chromosome damage, residual γ-H2AX foci), reduced p53 phosphorylation at Ser15, lower induction of p53 and CDKN1A proteins, and partial G1/S checkpoint defects. MADA patient fibroblasts; X-ray irradiation; chromosome damage analysis; γ-H2AX immunofluorescence; western blotting for p53/CDKN1A; flow cytometry cell cycle analysis Cell cycle Medium 18604166
2010 Cell-extrinsic factors (not intrinsic lamin A/C deficiency in lymphocytes or thymic stroma) cause severe lymphocyte developmental defects in Lmna(-/-) mice; Lmna(-/-) bone marrow reconstitutes normal T and B cell development in wild-type recipients, and Lmna(-/-) neonatal thymus transplantation supports normal thymocyte development. Bone marrow transplantation; neonatal thymus transplantation; flow cytometry for lymphocyte populations; T cell functional and MHC-restriction assays PloS one High 20405040
2023 LMNA mutant iPSC-CM nuclei have altered shape or increased size compared to healthy controls; the R249Q mutation additionally reduces nuclear stiffness and increases nuclear fragility; the degree of nuclear abnormalities corresponds to the degree of lamin A/C and lamin B1 mislocalization from the nuclear envelope, likely due to altered lamin A/C assembly. iPSC-CMs from LMNA mutant patients; nuclear morphometry; atomic force microscopy for nuclear stiffness; immunofluorescence for lamin A/C and B1 localization Molecular biology of the cell High 37585285
2011 The lamin A tail domain forms semi-stable ensemble structures; the HGPS Δ50 deletion makes the tail domain more compact and less heterogeneous in size; the ZMPSTE24 cleavage site on prelamin A orients to facilitate cleavage; altered structure of the Δ50 tail domain may explain changed protein-protein and protein-DNA interactions in HGPS pathogenesis. Replica exchange molecular dynamics simulations; in vitro thermodynamic stability measurements (circular dichroism, differential scanning fluorimetry) Journal of structural biology Medium 21635954
2022 Disease-causing LMNA mutations differentially affect myonuclear properties in Drosophila skeletal muscle: some mutant lamins increase nuclear deformability while others cause nucleo-cytoskeletal coupling defects associated with loss of microtubular nuclear caging; microtubule caging of the nucleus depends on Msp300 (KASH domain LINC complex component). Micropipette harpooning assay on larval body wall muscles in Drosophila lamin mutant models; nuclear deformability and intracellular force transmission measurements Frontiers in cell and developmental biology Medium 36120560
2024 Lamin A (LMNA) physically interacts with c-Myc and inhibits c-Myc transactivation; this interaction suppresses the expression of aminoacyl-tRNA synthetases EPRS and LARS, leading to reduced MAS activity, aerobic glycolysis, and neuroblastoma tumour progression; a small molecule (lobeline) that enhances LMNA-c-Myc interaction was identified. Co-immunoprecipitation and mass spectrometry; dual-luciferase reporter; chromatin immunoprecipitation; western blotting; RT-qPCR; neuroblastoma cell and organoid studies Clinical and translational medicine Medium 38769668
2019 Alternative 5' splice site selection in LMNA exon 11 (causing HGPS) is determined by an intricate interplay of primary sequence complementarity to U1 snRNA, RNA secondary structural elements near competing splice sites, and relative positioning of competing sites within the pre-mRNA, with distal position favored over proximal regardless of sequence. Targeted mutational analysis in cell-based splicing assay; SHAPE-MaP structural mapping of LMNA pre-mRNA; functional splice site competition experiments Nucleic acids research High 31006814
2010 Connexin 43 (Cx43) protein expression is reduced by ~40% and becomes internalized (mislocalized away from cell membrane) in neonatal cardiomyocytes transfected with LMNA E82K mutation; LMNA R644C does not affect Cx43; neither mutation affects Cx40 expression or localization. Transfection of wild-type and mutant LMNA into neonatal cardiomyocytes; confocal imaging; western blotting for Cx43 and Cx40 Chinese medical journal Medium 20497714
2013 TRF2 (shelterin subunit) levels are significantly reduced in early passage LMNA R133L and L140R mutant primary fibroblasts; TRF2 degradation correlates inversely with degree of abnormal nuclear morphology; hTERT introduction stabilizes telomeres but does not prevent TRF2 degradation; non-telomeric γ-H2AX foci (global DNA damage) are markedly increased in early passage LMNA mutant cells, indicating global genomic instability as an early event. Primary fibroblasts from LMNA mutant patients; early passage analysis; immunofluorescence for TRF2/γ-H2AX; hTERT introduction; telomere length analysis Frontiers in genetics Medium 23847654

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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