{"gene":"LMNB1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1995,"finding":"LMNB1 encodes an intermediate filament protein of the nuclear envelope whose transcription unit spans >45 kb and is organized into 11 exons: exon 1 codes for the amino-terminal head domain and first portion of the central rod domain, exons 2–6 code the central rod domain, and exons 7–11 code the carboxyl-terminal tail domain. Intron positions are conserved with other vertebrate lamin genes and most cytoplasmic intermediate filament protein genes.","method":"Genomic cloning and structural analysis of the human LMNB1 gene","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic structural determination, independently replicated in mouse (PMID:8586436), establishing conserved exon-intron architecture","pmids":["7557986","8586436"],"is_preprint":false},{"year":1995,"finding":"The mouse Lmnb1 gene spans ~43 kb and consists of 11 exons and 10 introns with conserved exon/intron organization shared among intermediate filament protein family genes. The presumptive promoter has high GC content, a CAAT box, and multiple SP1 sites but no classical TATA box, indicating a housekeeping gene promoter with a CpG island.","method":"Genomic cloning and structural analysis of the mouse Lmnb1 gene","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic structural determination with promoter characterization; consistent with human gene structure","pmids":["8586436"],"is_preprint":false},{"year":2013,"finding":"LMNB1 duplications in ADLD are intrachromosomal, non-recurrent, and arise through nonhomologous end joining or replication-based mechanisms (fork stalling and template switching / microhomology-mediated break-induced repair). The minimal duplicated region sufficient for disease was defined. All three LMNB1 alleles in ADLD patients show equal expression, indicating regulatory regions are maintained within the rearranged segment.","method":"Detailed molecular analysis of LMNB1 duplication junctions at nucleotide level; allele-specific expression analysis in patients' fibroblasts","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — largest collection of ADLD families analyzed, multiple orthogonal molecular methods (junction sequencing, expression analysis), replicated across families","pmids":["23649844"],"is_preprint":false},{"year":2013,"finding":"A missense variant A436T in LMNB1 (identified in NTD patients) was shown by fluorescence loss in photobleaching (FLIP) to compromise the stability of lamin B1 interaction within the nuclear lamina.","method":"Fluorescence loss in photobleaching (FLIP) analysis of LMNB1 A436T variant in cells","journal":"Birth defects research. Part A, Clinical and molecular teratology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single functional method (FLIP), no replication","pmids":["23733478"],"is_preprint":false},{"year":2020,"finding":"De novo missense mutations in LMNB1 cause impaired formation of the nuclear lamina. Two variants in the head group domain reduce nuclear localization of the protein and increase misshapen nuclei. A variant in the coil region leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts.","method":"Functional analysis of LMNB1 missense mutations by immunofluorescence/nuclear morphology assays and immunoblotting in patient lymphoblasts and transfected cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, morphology, protein level assays) across multiple independent de novo variants from seven unrelated individuals","pmids":["32910914"],"is_preprint":false},{"year":2021,"finding":"In DYT1 dystonia (TOR1A heterozygous mutation), LMNB1 is upregulated and exhibits abnormal subcellular distribution (nuclear-to-cytoplasmic mislocalization) specifically in cholinergic motor neurons. This dysregulation is causally linked to disease phenotypes (reduced neurite length, thickened nuclear lamina, disrupted nuclear morphology, impaired nucleocytoplasmic transport), as shRNA-mediated downregulation of LMNB1 largely ameliorates all cellular defects in DYT1 motor neurons.","method":"Human patient-specific motor neurons from iPSCs and direct conversion; shRNA knockdown of LMNB1; immunofluorescence; nucleocytoplasmic transport assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (iPSC differentiation, direct conversion, shRNA rescue, transport assays, morphology), two independent human neuron model systems","pmids":["33468570"],"is_preprint":false},{"year":2021,"finding":"LMNB1, as a component of the nuclear lamina, anchors heterochromatin and associates with transcription regulation, and its expression is upregulated with nuclear-to-cytoplasmic mislocalization in DYT1 dystonia neurons, as confirmed by GFP::LMNB1 CRISPR knockin iPSC modeling.","method":"CRISPR/Cas9 GFP::LMNB1 knockin iPSC line establishment; fluorescence co-localization","journal":"Stem cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, tool paper confirming localization; functional mechanism not directly tested here","pmids":["34438319"],"is_preprint":false},{"year":2022,"finding":"Knockdown of LMNB1 in lung adenocarcinoma cells decreases H3K9me3 protein expression, increases chromosome accessibility (by ATAC-seq), increases p53, p21, p16, and γ-H2AX expression, and increases senescence-positive cells, indicating that LMNB1 maintains heterochromatin compaction and suppresses DNA damage responses and cellular senescence.","method":"siRNA knockdown; ATAC-seq; immunofluorescence; immunoblotting; in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ATAC-seq, immunoblot, functional assays) in single lab","pmids":["35712471"],"is_preprint":false},{"year":2023,"finding":"LMNB1 directly interacts with the HBV enhancer II/basic core promoter (EnhII/BCP) DNA, as demonstrated by DNA pull-down assay. Overexpression of LMNB1 inhibits HBV promoter activity. ENPP1 interacts with LMNB1 and increases acetylation of LMNB1 at residues K111 and K261; LMNB1 acetylation mutants (111R, 261Q, 261R, 483Q, 483R) show increased HBV promoter activity, indicating that acetylation of LMNB1 at these sites is required for its transcriptional repression of HBV.","method":"DNA pull-down assay; luciferase reporter assay with HBV promoter/mutant constructs; acetylation site mutagenesis; ENPP1 overexpression/knockdown","journal":"Archives of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (DNA pulldown, reporter assay, mutagenesis) in single lab; mechanistic claims directly tested","pmids":["38265511"],"is_preprint":false},{"year":2023,"finding":"LMNB1 knockdown in ovarian cancer cells inhibits proliferation and migration by suppressing FGF1-mediated PI3K-Akt signaling pathway, as revealed by RNA-seq followed by functional validation.","method":"Stable LMNB1 knockdown; RNA-seq; CCK8, wound healing, transwell assays; xenograft models","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; pathway placement inferred from RNA-seq and standard phenotypic assays without direct mechanistic reconstitution","pmids":["37003558"],"is_preprint":false},{"year":2023,"finding":"MDM2 (an E3 ubiquitin ligase) increases p53 ubiquitination, which activates LMNB1 expression. METTL3-mediated m6A methylation of MDM2 mRNA stabilizes it via YTHDF1, thereby increasing MDM2 translation and downstream LMNB1 upregulation. Knockdown of LMNB1, MDM2, or METTL3 reduces mitochondrial damage and ferroptosis markers in LPS-treated kidney tubular epithelial cells.","method":"Gain/loss-of-function experiments; m6A methylation assays; co-immunoprecipitation; ubiquitination assays; in vivo CLP mouse model","journal":"European journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (m6A, ubiquitination, IP) in single lab; pathway position defined by epistasis-style rescue experiments","pmids":["37542992"],"is_preprint":false},{"year":2024,"finding":"WTAP promotes LMNB1 expression through m6A methylation modification of LMNB1 mRNA, as verified by meRIP assay, RIP assay, dual-luciferase reporter assay, and actinomycin D mRNA stability assay. LMNB1 in turn activates NF-κB and JAK2/STAT3 signaling pathways to promote inflammation and ferroptosis in kidney tubular epithelial cells.","method":"meRIP assay; RIP assay; dual-luciferase reporter assay; actinomycin D stability assay; western blot; flow cytometry; CLP mouse model","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods confirming m6A-LMNB1 axis; single lab","pmids":["38517565"],"is_preprint":false},{"year":2024,"finding":"LMNB1 promotes HCC cell proliferation by regulating CDKN1A (p21) expression, as shown by ChIP assay and pathway enrichment analysis with functional rescue experiments.","method":"LMNB1 knockdown; ChIP assay; gene ontology/pathway enrichment analysis; in vitro and in vivo proliferation assays","journal":"Current cancer drug targets","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP assay for pathway placement; single lab, single mechanistic experiment","pmids":["38778606"],"is_preprint":false},{"year":2024,"finding":"In autosomal dominant leukodystrophy (ADLD), classical ADLD is caused by intra-TAD duplications of LMNB1 resulting in a simple gene dose gain, while atypical ADLD results from inter-TAD deletions or duplications causing LMNB1 forebrain-specific misexpression by disrupting topologically associating domain (TAD) boundaries. Astrocytes are identified as key cellular players in ADLD pathology.","method":"High-throughput chromosome conformation capture (Hi-C); RNA sequencing; histopathological analysis of postmortem brain tissues; clinical/neuroradiological investigation of >20 families","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1 / Strong — Hi-C structural genomics combined with RNA-seq and histopathology across >20 families; multiple orthogonal methods establishing TAD-based pathomechanism","pmids":["39078102"],"is_preprint":false},{"year":2024,"finding":"LMNB1 knockdown in glioma cells reduces phosphorylation of Akt1/2/3 and expression of PI3K, AKT, and p-AKT proteins, placing LMNB1 upstream of the PI3K/Akt signaling pathway in glioma cell proliferation and migration.","method":"RNA interference; human phospho-kinase array; immunoblotting; xenograft models; wound healing and transwell assays","journal":"Neurochemical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; phospho-kinase array and immunoblot support pathway placement but no direct mechanistic reconstitution","pmids":["39636549"],"is_preprint":false},{"year":2024,"finding":"In Huntington's disease medium spiny neurons (MSNs), LMNB1 is greatly reduced and mislocalizes to the cytoplasm and axons. Treatment with KPT335 (nuclear export inhibitor) or HTT knockdown attenuates LMNB1 mislocalization and alleviates neuronal death, linking LMNB1 mislocalization to nucleocytoplasmic transport defects.","method":"hPSC-derived MSN differentiation; immunofluorescence for LMNB1 localization; KPT335 treatment; HTT knockdown; cell viability assays","journal":"Inflammation and regeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (rescue by nuclear export inhibition); single lab, multiple methods","pmids":["38360694"],"is_preprint":false},{"year":2025,"finding":"Transcription factor ZFP335 directly binds to the promoter of the Lmnb1 gene and regulates its transcription, as demonstrated by ChIP assay. Overexpression of Lmnb1 significantly rescues the impaired homeostatic proliferation of Zfp335-knockout T cells, establishing Lmnb1 as a direct downstream transcriptional target of Zfp335 required for naïve T cell homeostatic proliferation.","method":"ChIP assay; adoptive transfer model; Zfp335 conditional knockout; Lmnb1 overexpression rescue; RNA-seq; in vitro IL-7 proliferation assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay directly demonstrates promoter binding; genetic epistasis via rescue experiment; single lab","pmids":["41088342"],"is_preprint":false},{"year":2025,"finding":"Excess lamin B1 (LB1) elevates nuclear stiffness in neurons and impairs neuronal motility in confined spaces in vitro. In vivo, excess LB1 halts neuronal migration without altering laminar identity or overall gene expression. Cerebral organoids from LMNB1-duplication iPSCs exhibit impaired neuronal migration. Computational modeling and live imaging validate a temporal relationship between nuclear deformation and migration velocity.","method":"In vivo mouse cortical neuron overexpression; atomic force microscopy/nuclear stiffness measurement; live imaging in confined microchannels; cerebral organoids from patient iPSCs; computational modeling; electrophysiology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (nuclear stiffness assay, live imaging, organoids, in vivo) in single preprint lab; not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Conditional hypomorphic expression of Lamin B1 in B cells leads to elevated DNA damage, altered chromatin accessibility, and disrupted transcriptional profiles. Using sBLISS, non-random double-strand break hotspots are identified near transcriptional start sites and regulatory elements controlling translation and mRNA fate in GC B cells depleted of Lamin B1, indicating that LMNB1 protects fragile regulatory genomic regions.","method":"In vivo and in vitro B cell conditional hypomorphic Lamin B1 models; sBLISS (in situ labelling and sequencing of double-strand breaks); chromatin accessibility assays; transcriptomic profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sBLISS, chromatin accessibility, transcriptomics) with in vivo and in vitro models; single lab preprint","pmids":[],"is_preprint":true}],"current_model":"LMNB1 encodes a type B nuclear lamin that forms a major structural component of the nuclear lamina through its conserved intermediate filament domain architecture; it maintains nuclear envelope integrity and heterochromatin compaction (via H3K9me3), regulates nuclear stiffness and deformability to control neuronal migration, directly binds specific DNA regulatory sequences to repress transcription, is subject to acetylation (at K111, K261, K483) and m6A-mediated mRNA stabilization (by METTL3/WTAP), is transcriptionally regulated by ZFP335 binding its promoter, and acts downstream of TOR1A/MDM2-p53 signaling—with its dysregulation (overexpression, mislocalization, or loss) causing nucleocytoplasmic transport defects, impaired DNA damage repair, senescence, and contributing to diseases including ADLD (via gene dosage/TAD disruption), DYT1 dystonia, microcephaly, and Huntington's disease."},"narrative":{"mechanistic_narrative":"LMNB1 encodes a type B nuclear lamin built from a conserved intermediate-filament architecture (an N-terminal head, central rod, and C-terminal tail) that assembles into the nuclear lamina and underlies nuclear envelope integrity [PMID:7557986, PMID:8586436]. Disease-associated and de novo missense variants in the head and rod domains destabilize lamina incorporation, reduce nuclear localization, lower steady-state protein levels, and produce misshapen or condensed nuclei, establishing the protein's role in maintaining nuclear morphology [PMID:23733478, PMID:32910914]. Beyond structure, lamin B1 anchors heterochromatin and enforces its compaction: loss of LMNB1 decreases H3K9me3, opens chromatin accessibility, and triggers a DNA-damage and senescence program marked by p53, p21, p16, and γ-H2AX induction [PMID:35712471], and hypomorphic lamin B1 sensitizes regulatory genomic regions near transcription start sites to double-strand breaks. LMNB1 also engages transcriptional control directly, binding regulatory DNA to repress promoter activity in an acetylation-dependent manner (at K111/K261) [PMID:38265511]. Its abundance is set both transcriptionally, through direct promoter binding by ZFP335 [PMID:41088342], and post-transcriptionally, through m6A modification of its mRNA by WTAP and through an MDM2–p53 axis [PMID:37542992, PMID:38517565]. Nuclear lamin B1 dosage tunes nuclear stiffness and deformability to control neuronal migration, with excess lamin B1 arresting migration. Dysregulation of LMNB1—overexpression with nuclear-to-cytoplasmic mislocalization—drives nucleocytoplasmic transport defects and neuronal pathology in DYT1 dystonia and Huntington's disease [PMID:33468570, PMID:38360694], and altered LMNB1 gene dosage or TAD-boundary disruption causes autosomal dominant leukodystrophy (ADLD) [PMID:39078102].","teleology":[{"year":1995,"claim":"Establishing the genomic architecture of LMNB1 defined it as an intermediate-filament gene of the nuclear envelope with conserved head/rod/tail domain coding organization, framing all later structure-function interpretation.","evidence":"Genomic cloning and exon-intron analysis of human and mouse LMNB1/Lmnb1, including promoter characterization","pmids":["7557986","8586436"],"confidence":"High","gaps":["Does not establish lamina assembly mechanism or protein partners","Promoter regulation tested only by sequence features, not function"]},{"year":2013,"claim":"Detailed analysis of ADLD duplication junctions showed that the disease arises from a simple gene-dosage gain with regulatory regions preserved, defining LMNB1 copy number as the pathogenic variable.","evidence":"Nucleotide-level junction sequencing and allele-specific expression in patient fibroblasts across ADLD families","pmids":["23649844"],"confidence":"High","gaps":["Does not explain how dosage gain produces oligodendrocyte/myelin pathology","Cellular mechanism downstream of overexpression not addressed"]},{"year":2013,"claim":"A patient missense variant was shown to compromise lamin B1 stability within the lamina, providing the first functional link between point mutation and lamina integrity.","evidence":"FLIP analysis of the A436T variant in cells","pmids":["23733478"],"confidence":"Medium","gaps":["Single method (FLIP), no replication","No direct demonstration of disease causality"]},{"year":2020,"claim":"De novo missense mutations across head and rod domains were shown to impair lamina formation, reduce nuclear localization, and distort nuclear shape, establishing LMNB1 point mutations as a distinct mechanism from dosage gain.","evidence":"Localization, nuclear morphology, and protein-level assays in patient lymphoblasts and transfected cells from seven unrelated individuals","pmids":["32910914"],"confidence":"High","gaps":["Mechanism linking misshapen nuclei to neurodevelopmental phenotype not resolved","Loss-of-function vs dominant-negative contribution not separated"]},{"year":2021,"claim":"Patient-derived neuron models demonstrated that LMNB1 upregulation and nuclear-to-cytoplasmic mislocalization mediate DYT1 dystonia phenotypes, showing that LMNB1 acts downstream of TOR1A to control nuclear morphology and nucleocytoplasmic transport.","evidence":"iPSC and direct-conversion motor neurons, shRNA rescue, transport assays, and GFP::LMNB1 CRISPR knockin localization","pmids":["33468570","34438319"],"confidence":"High","gaps":["Molecular cause of mislocalization downstream of TOR1A unresolved","Whether transport defect is cause or consequence of lamina thickening unclear"]},{"year":2022,"claim":"Knockdown experiments established that LMNB1 maintains heterochromatin compaction via H3K9me3 and suppresses DNA damage and senescence, defining a chromatin-protective function beyond structural scaffolding.","evidence":"siRNA knockdown with ATAC-seq, immunoblotting, senescence markers, and xenografts in lung adenocarcinoma cells","pmids":["35712471"],"confidence":"Medium","gaps":["Single cell-type context","Direct mechanism linking lamina to H3K9me3 maintenance not shown"]},{"year":2023,"claim":"DNA pull-down and reporter assays showed LMNB1 directly binds regulatory DNA and represses transcription in an acetylation-dependent manner, extending its role to sequence-specific transcriptional control.","evidence":"DNA pull-down, luciferase reporter assays, acetylation-site mutagenesis, and ENPP1 manipulation on the HBV EnhII/BCP promoter","pmids":["38265511"],"confidence":"Medium","gaps":["Generality of direct DNA binding to endogenous host genes untested","Acetyltransferase/deacetylase responsible not identified"]},{"year":2023,"claim":"An MDM2–p53–LMNB1 axis regulated by METTL3-dependent m6A methylation was defined, placing LMNB1 expression downstream of an m6A-regulated stress signaling cascade.","evidence":"Gain/loss-of-function, m6A and ubiquitination assays, Co-IP, and CLP mouse model in kidney tubular epithelial cells","pmids":["37542992"],"confidence":"Medium","gaps":["Whether LMNB1 acts as effector or bystander in ferroptosis unclear","Direct vs indirect activation of LMNB1 by p53 not resolved"]},{"year":2024,"claim":"WTAP-mediated m6A methylation of LMNB1 mRNA was shown to stabilize it and drive downstream NF-κB and JAK2/STAT3 signaling, establishing direct post-transcriptional control of LMNB1 abundance.","evidence":"meRIP, RIP, dual-luciferase, and actinomycin D stability assays with CLP mouse model","pmids":["38517565"],"confidence":"Medium","gaps":["Mechanism by which lamin B1 activates cytoplasmic signaling pathways unexplained","Single disease context"]},{"year":2024,"claim":"Hi-C combined with RNA-seq and histopathology distinguished dosage-driven classical ADLD from TAD-boundary-disruption atypical ADLD, refining the genomic basis of LMNB1 leukodystrophy and implicating astrocytes.","evidence":"Hi-C, RNA-seq, and brain histopathology across more than 20 families","pmids":["39078102"],"confidence":"High","gaps":["Mechanism by which astrocyte misexpression causes demyelination not defined","Cell-type-specific consequences of forebrain misexpression not fully mapped"]},{"year":2024,"claim":"LMNB1 was placed within cancer proliferation programs, regulating CDKN1A/p21 and influencing PI3K/Akt signaling in hepatocellular carcinoma and glioma.","evidence":"Knockdown with ChIP, phospho-kinase arrays, pathway enrichment, and xenograft assays","pmids":["38778606","39636549"],"confidence":"Low","gaps":["Pathway placement inferred without direct biochemical reconstitution","Whether effects are lamin-structure-dependent or transcriptional unclear"]},{"year":2024,"claim":"Huntington's disease neuron models showed LMNB1 reduction and cytoplasmic mislocalization driving neuronal death rescuable by nuclear export inhibition, linking LMNB1 mislocalization to nucleocytoplasmic transport failure.","evidence":"hPSC-derived medium spiny neurons, immunofluorescence, KPT335 treatment, and HTT knockdown","pmids":["38360694"],"confidence":"Medium","gaps":["Causal direction between mislocalization and transport defect not fully resolved","Mechanism of LMNB1 nuclear export not identified"]},{"year":2025,"claim":"ZFP335 was identified as a direct transcriptional activator of Lmnb1 required for naïve T cell homeostatic proliferation, defining an upstream transcriptional regulator and a new physiological role.","evidence":"ChIP, conditional Zfp335 knockout, Lmnb1 overexpression rescue, and IL-7 proliferation assays","pmids":["41088342"],"confidence":"Medium","gaps":["How LMNB1 supports T cell proliferation mechanistically unclear","Single regulatory context"]},{"year":2025,"claim":"Lamin B1 dosage was shown to set nuclear stiffness and deformability that gates neuronal migration, providing a biophysical mechanism by which LMNB1 overexpression arrests migration.","evidence":"In vivo cortical neuron overexpression, atomic force microscopy, live imaging in microchannels, patient-iPSC cerebral organoids, and computational modeling (preprint)","pmids":[],"confidence":"Medium","gaps":["Not yet peer-reviewed","Link between migration arrest and ADLD/microcephaly phenotypes in patients not established"]},{"year":2025,"claim":"Hypomorphic Lamin B1 was shown to expose regulatory genomic regions to non-random double-strand breaks, demonstrating a genome-protective function at fragile regulatory loci.","evidence":"sBLISS, chromatin accessibility, and transcriptomic profiling in conditional B cell models (preprint)","pmids":[],"confidence":"Medium","gaps":["Not yet peer-reviewed","Mechanism of break protection at specific loci not defined"]},{"year":null,"claim":"How lamin B1's structural lamina role, its direct sequence-specific transcriptional repression, and its chromatin/genome-protective functions are mechanistically unified, and which of these mediates each disease phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model connecting domain mutations to specific molecular defects","Direct DNA-binding repression generality untested at endogenous loci","Causal contribution of dosage vs mislocalization vs loss across neurological diseases not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,13,4]}],"complexes":["nuclear lamina"],"partners":["ENPP1","ZFP335","WTAP","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20700","full_name":"Lamin-B1","aliases":[],"length_aa":586,"mass_kda":66.4,"function":"Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane (PubMed:28716252, PubMed:32910914). Lamins provide a framework for the nuclear envelope, bridging the nuclear envelope and chromatin, thereby playing an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics (PubMed:28716252, PubMed:32910914). The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively (PubMed:28716252, PubMed:32910914)","subcellular_location":"Nucleus lamina","url":"https://www.uniprot.org/uniprotkb/P20700/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMNB1","classification":"Not Classified","n_dependent_lines":132,"n_total_lines":1208,"dependency_fraction":0.10927152317880795},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000113368","cell_line_id":"CID000892","localizations":[{"compartment":"nuclear_membrane","grade":3}],"interactors":[{"gene":"BANF1","stoichiometry":0.2},{"gene":"DKC1","stoichiometry":0.2},{"gene":"KPNA6","stoichiometry":0.2},{"gene":"NSA2","stoichiometry":0.2},{"gene":"POLR2I","stoichiometry":0.2},{"gene":"RSL1D1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2},{"gene":"RANBP2","stoichiometry":0.2},{"gene":"NUP153","stoichiometry":0.2},{"gene":"MDH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000892","total_profiled":1310},"omim":[{"mim_id":"621061","title":"LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, ATYPICAL; ADLDAT","url":"https://www.omim.org/entry/621061"},{"mim_id":"619688","title":"LEUKODYSTROPHY, HYPOMYELINATING, 23, WITH ATAXIA, DEAFNESS, LIVER DYSFUNCTION, AND DILATED CARDIOMYOPATHY; HLD23","url":"https://www.omim.org/entry/619688"},{"mim_id":"619179","title":"MICROCEPHALY 26, PRIMARY, AUTOSOMAL DOMINANT; MCPH26","url":"https://www.omim.org/entry/619179"},{"mim_id":"616136","title":"RING FINGER PROTEIN 220; RNF220","url":"https://www.omim.org/entry/616136"},{"mim_id":"613333","title":"MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 3; MARCHF3","url":"https://www.omim.org/entry/613333"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":32.1},{"tissue":"lymphoid tissue","ntpm":45.9}],"url":"https://www.proteinatlas.org/search/LMNB1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P20700","domains":[{"cath_id":"2.60.40.1260","chopping":"432-549","consensus_level":"high","plddt":89.8999,"start":432,"end":549}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20700","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20700-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20700-F1-predicted_aligned_error_v6.png","plddt_mean":82.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMNB1","jax_strain_url":"https://www.jax.org/strain/search?query=LMNB1"},"sequence":{"accession":"P20700","fasta_url":"https://rest.uniprot.org/uniprotkb/P20700.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20700/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20700"}},"corpus_meta":[{"pmid":"7557986","id":"PMC_7557986","title":"Structural organization of the human gene (LMNB1) encoding nuclear lamin B1.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7557986","citation_count":111,"is_preprint":false},{"pmid":"19522540","id":"PMC_19522540","title":"Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients.","date":"2010","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19522540","citation_count":111,"is_preprint":false},{"pmid":"8838815","id":"PMC_8838815","title":"Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8838815","citation_count":90,"is_preprint":false},{"pmid":"30394198","id":"PMC_30394198","title":"GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30394198","citation_count":73,"is_preprint":false},{"pmid":"26053668","id":"PMC_26053668","title":"LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course.","date":"2015","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26053668","citation_count":39,"is_preprint":false},{"pmid":"33468570","id":"PMC_33468570","title":"Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33468570","citation_count":39,"is_preprint":false},{"pmid":"23649844","id":"PMC_23649844","title":"Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.","date":"2013","source":"Human 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Intron positions are conserved with other vertebrate lamin genes and most cytoplasmic intermediate filament protein genes.\",\n      \"method\": \"Genomic cloning and structural analysis of the human LMNB1 gene\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic structural determination, independently replicated in mouse (PMID:8586436), establishing conserved exon-intron architecture\",\n      \"pmids\": [\"7557986\", \"8586436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The mouse Lmnb1 gene spans ~43 kb and consists of 11 exons and 10 introns with conserved exon/intron organization shared among intermediate filament protein family genes. The presumptive promoter has high GC content, a CAAT box, and multiple SP1 sites but no classical TATA box, indicating a housekeeping gene promoter with a CpG island.\",\n      \"method\": \"Genomic cloning and structural analysis of the mouse Lmnb1 gene\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic structural determination with promoter characterization; consistent with human gene structure\",\n      \"pmids\": [\"8586436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LMNB1 duplications in ADLD are intrachromosomal, non-recurrent, and arise through nonhomologous end joining or replication-based mechanisms (fork stalling and template switching / microhomology-mediated break-induced repair). The minimal duplicated region sufficient for disease was defined. All three LMNB1 alleles in ADLD patients show equal expression, indicating regulatory regions are maintained within the rearranged segment.\",\n      \"method\": \"Detailed molecular analysis of LMNB1 duplication junctions at nucleotide level; allele-specific expression analysis in patients' fibroblasts\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — largest collection of ADLD families analyzed, multiple orthogonal molecular methods (junction sequencing, expression analysis), replicated across families\",\n      \"pmids\": [\"23649844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense variant A436T in LMNB1 (identified in NTD patients) was shown by fluorescence loss in photobleaching (FLIP) to compromise the stability of lamin B1 interaction within the nuclear lamina.\",\n      \"method\": \"Fluorescence loss in photobleaching (FLIP) analysis of LMNB1 A436T variant in cells\",\n      \"journal\": \"Birth defects research. Part A, Clinical and molecular teratology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single functional method (FLIP), no replication\",\n      \"pmids\": [\"23733478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"De novo missense mutations in LMNB1 cause impaired formation of the nuclear lamina. Two variants in the head group domain reduce nuclear localization of the protein and increase misshapen nuclei. A variant in the coil region leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts.\",\n      \"method\": \"Functional analysis of LMNB1 missense mutations by immunofluorescence/nuclear morphology assays and immunoblotting in patient lymphoblasts and transfected cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, morphology, protein level assays) across multiple independent de novo variants from seven unrelated individuals\",\n      \"pmids\": [\"32910914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In DYT1 dystonia (TOR1A heterozygous mutation), LMNB1 is upregulated and exhibits abnormal subcellular distribution (nuclear-to-cytoplasmic mislocalization) specifically in cholinergic motor neurons. This dysregulation is causally linked to disease phenotypes (reduced neurite length, thickened nuclear lamina, disrupted nuclear morphology, impaired nucleocytoplasmic transport), as shRNA-mediated downregulation of LMNB1 largely ameliorates all cellular defects in DYT1 motor neurons.\",\n      \"method\": \"Human patient-specific motor neurons from iPSCs and direct conversion; shRNA knockdown of LMNB1; immunofluorescence; nucleocytoplasmic transport assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (iPSC differentiation, direct conversion, shRNA rescue, transport assays, morphology), two independent human neuron model systems\",\n      \"pmids\": [\"33468570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LMNB1, as a component of the nuclear lamina, anchors heterochromatin and associates with transcription regulation, and its expression is upregulated with nuclear-to-cytoplasmic mislocalization in DYT1 dystonia neurons, as confirmed by GFP::LMNB1 CRISPR knockin iPSC modeling.\",\n      \"method\": \"CRISPR/Cas9 GFP::LMNB1 knockin iPSC line establishment; fluorescence co-localization\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, tool paper confirming localization; functional mechanism not directly tested here\",\n      \"pmids\": [\"34438319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of LMNB1 in lung adenocarcinoma cells decreases H3K9me3 protein expression, increases chromosome accessibility (by ATAC-seq), increases p53, p21, p16, and γ-H2AX expression, and increases senescence-positive cells, indicating that LMNB1 maintains heterochromatin compaction and suppresses DNA damage responses and cellular senescence.\",\n      \"method\": \"siRNA knockdown; ATAC-seq; immunofluorescence; immunoblotting; in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ATAC-seq, immunoblot, functional assays) in single lab\",\n      \"pmids\": [\"35712471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMNB1 directly interacts with the HBV enhancer II/basic core promoter (EnhII/BCP) DNA, as demonstrated by DNA pull-down assay. Overexpression of LMNB1 inhibits HBV promoter activity. ENPP1 interacts with LMNB1 and increases acetylation of LMNB1 at residues K111 and K261; LMNB1 acetylation mutants (111R, 261Q, 261R, 483Q, 483R) show increased HBV promoter activity, indicating that acetylation of LMNB1 at these sites is required for its transcriptional repression of HBV.\",\n      \"method\": \"DNA pull-down assay; luciferase reporter assay with HBV promoter/mutant constructs; acetylation site mutagenesis; ENPP1 overexpression/knockdown\",\n      \"journal\": \"Archives of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (DNA pulldown, reporter assay, mutagenesis) in single lab; mechanistic claims directly tested\",\n      \"pmids\": [\"38265511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMNB1 knockdown in ovarian cancer cells inhibits proliferation and migration by suppressing FGF1-mediated PI3K-Akt signaling pathway, as revealed by RNA-seq followed by functional validation.\",\n      \"method\": \"Stable LMNB1 knockdown; RNA-seq; CCK8, wound healing, transwell assays; xenograft models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; pathway placement inferred from RNA-seq and standard phenotypic assays without direct mechanistic reconstitution\",\n      \"pmids\": [\"37003558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MDM2 (an E3 ubiquitin ligase) increases p53 ubiquitination, which activates LMNB1 expression. METTL3-mediated m6A methylation of MDM2 mRNA stabilizes it via YTHDF1, thereby increasing MDM2 translation and downstream LMNB1 upregulation. Knockdown of LMNB1, MDM2, or METTL3 reduces mitochondrial damage and ferroptosis markers in LPS-treated kidney tubular epithelial cells.\",\n      \"method\": \"Gain/loss-of-function experiments; m6A methylation assays; co-immunoprecipitation; ubiquitination assays; in vivo CLP mouse model\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (m6A, ubiquitination, IP) in single lab; pathway position defined by epistasis-style rescue experiments\",\n      \"pmids\": [\"37542992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP promotes LMNB1 expression through m6A methylation modification of LMNB1 mRNA, as verified by meRIP assay, RIP assay, dual-luciferase reporter assay, and actinomycin D mRNA stability assay. LMNB1 in turn activates NF-κB and JAK2/STAT3 signaling pathways to promote inflammation and ferroptosis in kidney tubular epithelial cells.\",\n      \"method\": \"meRIP assay; RIP assay; dual-luciferase reporter assay; actinomycin D stability assay; western blot; flow cytometry; CLP mouse model\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods confirming m6A-LMNB1 axis; single lab\",\n      \"pmids\": [\"38517565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LMNB1 promotes HCC cell proliferation by regulating CDKN1A (p21) expression, as shown by ChIP assay and pathway enrichment analysis with functional rescue experiments.\",\n      \"method\": \"LMNB1 knockdown; ChIP assay; gene ontology/pathway enrichment analysis; in vitro and in vivo proliferation assays\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP assay for pathway placement; single lab, single mechanistic experiment\",\n      \"pmids\": [\"38778606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In autosomal dominant leukodystrophy (ADLD), classical ADLD is caused by intra-TAD duplications of LMNB1 resulting in a simple gene dose gain, while atypical ADLD results from inter-TAD deletions or duplications causing LMNB1 forebrain-specific misexpression by disrupting topologically associating domain (TAD) boundaries. Astrocytes are identified as key cellular players in ADLD pathology.\",\n      \"method\": \"High-throughput chromosome conformation capture (Hi-C); RNA sequencing; histopathological analysis of postmortem brain tissues; clinical/neuroradiological investigation of >20 families\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Hi-C structural genomics combined with RNA-seq and histopathology across >20 families; multiple orthogonal methods establishing TAD-based pathomechanism\",\n      \"pmids\": [\"39078102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LMNB1 knockdown in glioma cells reduces phosphorylation of Akt1/2/3 and expression of PI3K, AKT, and p-AKT proteins, placing LMNB1 upstream of the PI3K/Akt signaling pathway in glioma cell proliferation and migration.\",\n      \"method\": \"RNA interference; human phospho-kinase array; immunoblotting; xenograft models; wound healing and transwell assays\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; phospho-kinase array and immunoblot support pathway placement but no direct mechanistic reconstitution\",\n      \"pmids\": [\"39636549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Huntington's disease medium spiny neurons (MSNs), LMNB1 is greatly reduced and mislocalizes to the cytoplasm and axons. Treatment with KPT335 (nuclear export inhibitor) or HTT knockdown attenuates LMNB1 mislocalization and alleviates neuronal death, linking LMNB1 mislocalization to nucleocytoplasmic transport defects.\",\n      \"method\": \"hPSC-derived MSN differentiation; immunofluorescence for LMNB1 localization; KPT335 treatment; HTT knockdown; cell viability assays\",\n      \"journal\": \"Inflammation and regeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (rescue by nuclear export inhibition); single lab, multiple methods\",\n      \"pmids\": [\"38360694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Transcription factor ZFP335 directly binds to the promoter of the Lmnb1 gene and regulates its transcription, as demonstrated by ChIP assay. Overexpression of Lmnb1 significantly rescues the impaired homeostatic proliferation of Zfp335-knockout T cells, establishing Lmnb1 as a direct downstream transcriptional target of Zfp335 required for naïve T cell homeostatic proliferation.\",\n      \"method\": \"ChIP assay; adoptive transfer model; Zfp335 conditional knockout; Lmnb1 overexpression rescue; RNA-seq; in vitro IL-7 proliferation assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay directly demonstrates promoter binding; genetic epistasis via rescue experiment; single lab\",\n      \"pmids\": [\"41088342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Excess lamin B1 (LB1) elevates nuclear stiffness in neurons and impairs neuronal motility in confined spaces in vitro. In vivo, excess LB1 halts neuronal migration without altering laminar identity or overall gene expression. Cerebral organoids from LMNB1-duplication iPSCs exhibit impaired neuronal migration. Computational modeling and live imaging validate a temporal relationship between nuclear deformation and migration velocity.\",\n      \"method\": \"In vivo mouse cortical neuron overexpression; atomic force microscopy/nuclear stiffness measurement; live imaging in confined microchannels; cerebral organoids from patient iPSCs; computational modeling; electrophysiology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (nuclear stiffness assay, live imaging, organoids, in vivo) in single preprint lab; not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional hypomorphic expression of Lamin B1 in B cells leads to elevated DNA damage, altered chromatin accessibility, and disrupted transcriptional profiles. Using sBLISS, non-random double-strand break hotspots are identified near transcriptional start sites and regulatory elements controlling translation and mRNA fate in GC B cells depleted of Lamin B1, indicating that LMNB1 protects fragile regulatory genomic regions.\",\n      \"method\": \"In vivo and in vitro B cell conditional hypomorphic Lamin B1 models; sBLISS (in situ labelling and sequencing of double-strand breaks); chromatin accessibility assays; transcriptomic profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sBLISS, chromatin accessibility, transcriptomics) with in vivo and in vitro models; single lab preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LMNB1 encodes a type B nuclear lamin that forms a major structural component of the nuclear lamina through its conserved intermediate filament domain architecture; it maintains nuclear envelope integrity and heterochromatin compaction (via H3K9me3), regulates nuclear stiffness and deformability to control neuronal migration, directly binds specific DNA regulatory sequences to repress transcription, is subject to acetylation (at K111, K261, K483) and m6A-mediated mRNA stabilization (by METTL3/WTAP), is transcriptionally regulated by ZFP335 binding its promoter, and acts downstream of TOR1A/MDM2-p53 signaling—with its dysregulation (overexpression, mislocalization, or loss) causing nucleocytoplasmic transport defects, impaired DNA damage repair, senescence, and contributing to diseases including ADLD (via gene dosage/TAD disruption), DYT1 dystonia, microcephaly, and Huntington's disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMNB1 encodes a type B nuclear lamin built from a conserved intermediate-filament architecture (an N-terminal head, central rod, and C-terminal tail) that assembles into the nuclear lamina and underlies nuclear envelope integrity [#0, #1]. Disease-associated and de novo missense variants in the head and rod domains destabilize lamina incorporation, reduce nuclear localization, lower steady-state protein levels, and produce misshapen or condensed nuclei, establishing the protein's role in maintaining nuclear morphology [#3, #4]. Beyond structure, lamin B1 anchors heterochromatin and enforces its compaction: loss of LMNB1 decreases H3K9me3, opens chromatin accessibility, and triggers a DNA-damage and senescence program marked by p53, p21, p16, and \\u03b3-H2AX induction [#7], and hypomorphic lamin B1 sensitizes regulatory genomic regions near transcription start sites to double-strand breaks [#18]. LMNB1 also engages transcriptional control directly, binding regulatory DNA to repress promoter activity in an acetylation-dependent manner (at K111/K261) [#8]. Its abundance is set both transcriptionally, through direct promoter binding by ZFP335 [#16], and post-transcriptionally, through m6A modification of its mRNA by WTAP and through an MDM2\\u2013p53 axis [#10, #11]. Nuclear lamin B1 dosage tunes nuclear stiffness and deformability to control neuronal migration, with excess lamin B1 arresting migration [#17]. Dysregulation of LMNB1\\u2014overexpression with nuclear-to-cytoplasmic mislocalization\\u2014drives nucleocytoplasmic transport defects and neuronal pathology in DYT1 dystonia and Huntington's disease [#5, #15], and altered LMNB1 gene dosage or TAD-boundary disruption causes autosomal dominant leukodystrophy (ADLD) [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the genomic architecture of LMNB1 defined it as an intermediate-filament gene of the nuclear envelope with conserved head/rod/tail domain coding organization, framing all later structure-function interpretation.\",\n      \"evidence\": \"Genomic cloning and exon-intron analysis of human and mouse LMNB1/Lmnb1, including promoter characterization\",\n      \"pmids\": [\"7557986\", \"8586436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish lamina assembly mechanism or protein partners\", \"Promoter regulation tested only by sequence features, not function\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Detailed analysis of ADLD duplication junctions showed that the disease arises from a simple gene-dosage gain with regulatory regions preserved, defining LMNB1 copy number as the pathogenic variable.\",\n      \"evidence\": \"Nucleotide-level junction sequencing and allele-specific expression in patient fibroblasts across ADLD families\",\n      \"pmids\": [\"23649844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain how dosage gain produces oligodendrocyte/myelin pathology\", \"Cellular mechanism downstream of overexpression not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A patient missense variant was shown to compromise lamin B1 stability within the lamina, providing the first functional link between point mutation and lamina integrity.\",\n      \"evidence\": \"FLIP analysis of the A436T variant in cells\",\n      \"pmids\": [\"23733478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (FLIP), no replication\", \"No direct demonstration of disease causality\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"De novo missense mutations across head and rod domains were shown to impair lamina formation, reduce nuclear localization, and distort nuclear shape, establishing LMNB1 point mutations as a distinct mechanism from dosage gain.\",\n      \"evidence\": \"Localization, nuclear morphology, and protein-level assays in patient lymphoblasts and transfected cells from seven unrelated individuals\",\n      \"pmids\": [\"32910914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking misshapen nuclei to neurodevelopmental phenotype not resolved\", \"Loss-of-function vs dominant-negative contribution not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Patient-derived neuron models demonstrated that LMNB1 upregulation and nuclear-to-cytoplasmic mislocalization mediate DYT1 dystonia phenotypes, showing that LMNB1 acts downstream of TOR1A to control nuclear morphology and nucleocytoplasmic transport.\",\n      \"evidence\": \"iPSC and direct-conversion motor neurons, shRNA rescue, transport assays, and GFP::LMNB1 CRISPR knockin localization\",\n      \"pmids\": [\"33468570\", \"34438319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of mislocalization downstream of TOR1A unresolved\", \"Whether transport defect is cause or consequence of lamina thickening unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Knockdown experiments established that LMNB1 maintains heterochromatin compaction via H3K9me3 and suppresses DNA damage and senescence, defining a chromatin-protective function beyond structural scaffolding.\",\n      \"evidence\": \"siRNA knockdown with ATAC-seq, immunoblotting, senescence markers, and xenografts in lung adenocarcinoma cells\",\n      \"pmids\": [\"35712471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-type context\", \"Direct mechanism linking lamina to H3K9me3 maintenance not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"DNA pull-down and reporter assays showed LMNB1 directly binds regulatory DNA and represses transcription in an acetylation-dependent manner, extending its role to sequence-specific transcriptional control.\",\n      \"evidence\": \"DNA pull-down, luciferase reporter assays, acetylation-site mutagenesis, and ENPP1 manipulation on the HBV EnhII/BCP promoter\",\n      \"pmids\": [\"38265511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of direct DNA binding to endogenous host genes untested\", \"Acetyltransferase/deacetylase responsible not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"An MDM2\\u2013p53\\u2013LMNB1 axis regulated by METTL3-dependent m6A methylation was defined, placing LMNB1 expression downstream of an m6A-regulated stress signaling cascade.\",\n      \"evidence\": \"Gain/loss-of-function, m6A and ubiquitination assays, Co-IP, and CLP mouse model in kidney tubular epithelial cells\",\n      \"pmids\": [\"37542992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LMNB1 acts as effector or bystander in ferroptosis unclear\", \"Direct vs indirect activation of LMNB1 by p53 not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"WTAP-mediated m6A methylation of LMNB1 mRNA was shown to stabilize it and drive downstream NF-\\u03baB and JAK2/STAT3 signaling, establishing direct post-transcriptional control of LMNB1 abundance.\",\n      \"evidence\": \"meRIP, RIP, dual-luciferase, and actinomycin D stability assays with CLP mouse model\",\n      \"pmids\": [\"38517565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which lamin B1 activates cytoplasmic signaling pathways unexplained\", \"Single disease context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Hi-C combined with RNA-seq and histopathology distinguished dosage-driven classical ADLD from TAD-boundary-disruption atypical ADLD, refining the genomic basis of LMNB1 leukodystrophy and implicating astrocytes.\",\n      \"evidence\": \"Hi-C, RNA-seq, and brain histopathology across more than 20 families\",\n      \"pmids\": [\"39078102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which astrocyte misexpression causes demyelination not defined\", \"Cell-type-specific consequences of forebrain misexpression not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"LMNB1 was placed within cancer proliferation programs, regulating CDKN1A/p21 and influencing PI3K/Akt signaling in hepatocellular carcinoma and glioma.\",\n      \"evidence\": \"Knockdown with ChIP, phospho-kinase arrays, pathway enrichment, and xenograft assays\",\n      \"pmids\": [\"38778606\", \"39636549\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred without direct biochemical reconstitution\", \"Whether effects are lamin-structure-dependent or transcriptional unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Huntington's disease neuron models showed LMNB1 reduction and cytoplasmic mislocalization driving neuronal death rescuable by nuclear export inhibition, linking LMNB1 mislocalization to nucleocytoplasmic transport failure.\",\n      \"evidence\": \"hPSC-derived medium spiny neurons, immunofluorescence, KPT335 treatment, and HTT knockdown\",\n      \"pmids\": [\"38360694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between mislocalization and transport defect not fully resolved\", \"Mechanism of LMNB1 nuclear export not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZFP335 was identified as a direct transcriptional activator of Lmnb1 required for naïve T cell homeostatic proliferation, defining an upstream transcriptional regulator and a new physiological role.\",\n      \"evidence\": \"ChIP, conditional Zfp335 knockout, Lmnb1 overexpression rescue, and IL-7 proliferation assays\",\n      \"pmids\": [\"41088342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LMNB1 supports T cell proliferation mechanistically unclear\", \"Single regulatory context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lamin B1 dosage was shown to set nuclear stiffness and deformability that gates neuronal migration, providing a biophysical mechanism by which LMNB1 overexpression arrests migration.\",\n      \"evidence\": \"In vivo cortical neuron overexpression, atomic force microscopy, live imaging in microchannels, patient-iPSC cerebral organoids, and computational modeling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Link between migration arrest and ADLD/microcephaly phenotypes in patients not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Hypomorphic Lamin B1 was shown to expose regulatory genomic regions to non-random double-strand breaks, demonstrating a genome-protective function at fragile regulatory loci.\",\n      \"evidence\": \"sBLISS, chromatin accessibility, and transcriptomic profiling in conditional B cell models (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Mechanism of break protection at specific loci not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How lamin B1's structural lamina role, its direct sequence-specific transcriptional repression, and its chromatin/genome-protective functions are mechanistically unified, and which of these mediates each disease phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model connecting domain mutations to specific molecular defects\", \"Direct DNA-binding repression generality untested at endogenous loci\", \"Causal contribution of dosage vs mislocalization vs loss across neurological diseases not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 13, 4]}\n    ],\n    \"complexes\": [\"nuclear lamina\"],\n    \"partners\": [\"ENPP1\", \"ZFP335\", \"WTAP\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}