{"gene":"LAMB1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1987,"finding":"Human LAMB1 encodes a 1786-amino acid multidomain protein with two types of internal homology repeats: type A repeats (~50 aa, 8 cysteines each) clustered near the NH2-terminus in two clusters of 5 and 8 consecutive repeats, and type B repeats (~40 aa) near the COOH-terminus, plus globular regions and helical structures. The LAMB1 gene was mapped to chromosome 7q22 by somatic cell hybrid methodology and in situ hybridization.","method":"cDNA cloning, sequence analysis, somatic cell hybrid methodology, in situ hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete cDNA sequence with domain architecture established by direct molecular cloning and chromosomal mapping; foundational characterization replicated in subsequent work","pmids":["3611077"],"is_preprint":false},{"year":1997,"finding":"The LAMB1 gene is regulated by retinoic acid (RA) and cAMP/PKA signaling. In F9 teratocarcinoma cells partially deficient in PKA activity, cAMP-associated activation of the LAMB1 DNase I hypersensitivity site 2 enhancer was significantly decreased. EMSA showed reduced protein binding at the C2 motif within this enhancer in PKA-deficient cells after RA+cAMP treatment, and in vitro phosphorylation failed to rescue C2 binding, indicating PKA is required for induction of the C2-binding protein.","method":"Stable transfection of dominant-negative PKA regulatory subunit, chloramphenicol acetyltransferase (CAT) assay, DNase I hypersensitivity, electrophoretic mobility shift assay (EMSA), in vitro phosphorylation","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CAT assay, DNase I hypersensitivity, EMSA) in a single lab establishing PKA involvement in LAMB1 enhancer activation","pmids":["9419418"],"is_preprint":false},{"year":1997,"finding":"The first 0.7 kb of LAMB1 5' flanking sequence is sufficient to direct expression in prospermatogonia cells of the testis, while additional elements within 4 kb 5' of the transcription start site are required for expression in oocytes and epithelial cells of mesonephric ducts, ductus deferens, ductus epididymis, and seminal vesicles.","method":"Transgenic mouse lines with LAMB1 promoter fragments fused to lacZ reporter gene; beta-galactosidase staining","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo promoter dissection using transgenic mice with two different promoter-reporter constructs, single lab","pmids":["9447707"],"is_preprint":false},{"year":2015,"finding":"A dominant missense mutation in mouse Lamb1 (lamb1t) causes a dystonia-like movement disorder. Cerebellar recordings in awake mice detected abnormal output from Purkinje cells and their deep cerebellar nucleus targets during abnormal postures, implicating Lamb1 in synapse structure/plasticity in CNS circuits that regulate movement. The phenotype depends on interaction of brain and spinal cord circuits.","method":"SNP mapping, exome sequencing, in vivo electrophysiology (awake cerebellar recordings), electromyography showing co-contraction of opposing muscle groups","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — causative mutation identified by exome sequencing, phenotype characterized by multiple orthogonal methods (EMG, awake neural recording), published in peer-reviewed journal","pmids":["26705335"],"is_preprint":false},{"year":2021,"finding":"LAMB1 truncating variants that escape nonsense-mediated mRNA decay produce truncated LAMB1 proteins that are trapped in the cytosol rather than being secreted to the extracellular matrix, as demonstrated using two antibodies recognizing N- and C-terminal parts of LAMB1 in endogenous patient fibroblasts. These variants cause a leukoencephalopathy with hippocampal memory defects.","method":"Western blotting with N- and C-terminal antibodies, gene-based collapsing test of rare protein-truncating variants in exome data, patient fibroblast analysis","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization experiment in patient-derived cells using two orthogonal antibodies, single lab","pmids":["34606115"],"is_preprint":false},{"year":2021,"finding":"LAMB1 promotes gastric cancer cell growth and motility. The ERK inhibitor U0126 reduces LAMB1 expression, and c-Jun was shown to directly bind the LAMB1 promoter and regulate its transcription via the ERK pathway.","method":"LAMB1 overexpression and knockdown in gastric cancer cells, ERK inhibitor treatment, chromatin immunoprecipitation (c-Jun binding to LAMB1 promoter), cell proliferation/invasion/migration assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP combined with loss-of-function and pharmacological inhibition, single lab","pmids":["33435161"],"is_preprint":false},{"year":2022,"finding":"DDX24 binds the mRNA of LAMB1 at nucleotides 618-624 and increases LAMB1 mRNA stability in a manner dependent on the interaction between nucleolin and the C-terminal region of DDX24, thereby promoting HCC cell migration and proliferation.","method":"RNA immunoprecipitation, mRNA stability assay, DDX24 overexpression/knockdown, Co-IP (DDX24-nucleolin interaction), in vitro and in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct RNA-binding site identified by RIP, mRNA stability measured, protein interaction by Co-IP, functional rescue experiments in vitro and in vivo in a single rigorous study","pmids":["35763670"],"is_preprint":false},{"year":2023,"finding":"LAMB1 binds FAK (focal adhesion kinase) and this interaction converts mechanical substrate stiffness signals into biochemical signaling that controls MEK1/2 activity during dentinogenesis in odontoblast-like cells.","method":"Immunoprecipitation (LAMB1-FAK interaction), immunofluorescent staining, Western blotting, polydimethylsiloxane substrates of varying stiffness, qPCR","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct LAMB1-FAK interaction shown by immunoprecipitation with functional downstream pathway (MEK1/2) readout, single lab","pmids":["36519511"],"is_preprint":false},{"year":2025,"finding":"Vascular LAMB1 provides a haptotactic gradient sensed by Itga6 (integrin alpha-6) on retinal microglial precursors. Lamb1-Itga6 engagement activates Rac1 signaling, promoting F-actin polarization and directional migration of microglial precursors into the developing retina via blood vessels. Endothelial-specific LAMB1 deficiency in mice impairs microglial precursor settlement.","method":"Zebrafish live imaging, genetic interference with Lamb1/Itga6 axis, endothelial-specific conditional knockout in mice, F-actin polarization assay, Rac1 activity assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conserved mechanism validated in two organisms (zebrafish and mouse) with multiple orthogonal methods including conditional KO, live imaging, and signaling readouts","pmids":["41206867"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, the LAMB1 ortholog LanB1 localizes to the blood-brain barrier (BBB) in adult fly brains and is expressed in a subset of glial cells. Knockdown of LanB1 in the BBB results in short lifespan and locomotor defects. In vitro assay in HEK293T cells showed that late-truncated LAMB1 is uniquely detected as a monomer in culture medium (unlike full-length or early frameshift variants), suggesting dominant leukoencephalopathy variants act through a gain-of-function mechanism via secretion of truncated monomeric protein.","method":"Drosophila LanB1 knockdown (RNAi), immunofluorescence localization, in vivo overexpression/rescue experiments with variant alleles, HEK293T cell expression assay with Western blotting","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vivo Drosophila genetics, in vitro human cell assay) in a single study establishing BBB localization and gain-of-function mechanism for truncation variants","pmids":["40237576"],"is_preprint":false},{"year":2025,"finding":"LAMB1 promotes glioma cell glycolysis and proliferation via activation of the NF-κB pathway, which upregulates hexokinase 2 (HK2). Inhibition of NF-κB by Bay 11-7082 phenocopied LAMB1 knockdown in suppressing glycolysis (measured by ECAR) and tumor growth, and reducing TMZ sensitivity.","method":"LAMB1 overexpression/knockdown in glioma cells, Seahorse ECAR measurement, NF-κB pathway inhibitor (Bay 11-7082), Western blotting for HK2/NF-κB components, subcutaneous tumor model","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by pharmacological inhibitor combined with loss/gain-of-function and metabolic readouts, single lab","pmids":["39920513"],"is_preprint":false},{"year":2025,"finding":"LAMB1 knockdown suppresses Wnt/β-catenin signaling in endothelial cells, reducing expression of wnt3a, GSK-3β, β-catenin, and VEGFA, and impairing HUVEC proliferation, migration, and tube formation. The Wnt agonist HY-141873 partially rescued these defects, placing LAMB1 upstream of Wnt/β-catenin/VEGFA in angiogenesis during fracture healing.","method":"siRNA-mediated LAMB1 knockdown in HUVECs, Western blotting, Wnt agonist rescue experiment, tube formation assay, transwell migration assay, scRNA-seq pseudotime analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by pharmacological rescue of KD phenotype, multiple functional readouts, single lab","pmids":["40221061"],"is_preprint":false},{"year":2026,"finding":"Recombinant LAMB1 protein (rLAMB1) promotes osteoclast formation by activating the MAPK signaling pathway (phosphorylation of p38 and JNK). Muscle-secreted LAMB1 and CTGF were upregulated in bone in an OVX osteoporosis model and mediated bone-muscle crosstalk through MAPK activation.","method":"In vitro osteoclastogenesis assay with recombinant LAMB1, TRAP staining, Western blotting for MAPK phosphorylation, dual-tissue transcriptomics, protein-peptide docking","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — recombinant protein in vitro assay with MAPK readout, but single lab and limited mechanistic detail on receptor","pmids":["41690031"],"is_preprint":false},{"year":2026,"finding":"LAMB1 silencing in trophoblast (HTR-8/SVneo) cells modulates the COL3A1/RAC1 axis: LAMB1 knockdown reduced pro-inflammatory cytokine levels, enhanced trophoblast proliferation/migration/invasion, and improved pregnancy outcomes in an LPS-induced SCH rat model. LAMB1 expression was positively correlated with COL3A1 and inversely with RAC1 in SCH tissues.","method":"LAMB1 knockdown (siRNA/in vivo), proteomic and transcriptomic analysis, in vivo SCH rat model, trophoblast functional assays (proliferation, migration, invasion), cytokine measurement","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined molecular and functional readouts, single lab","pmids":["41840580"],"is_preprint":false},{"year":2025,"finding":"In a cortical migration disorder model (co-activation of LIN28A and CTNNB1), spatially resolved proteome analysis revealed imbalances of extracellular matrix protein LAMB1 and its receptors RPSA and ITGB1, accompanied by a porous pial border and overmigration of neural cells, suggesting LAMB1 and its receptors are required for pial border integrity and cortical neuronal migration.","method":"Spatially resolved proteomics, mouse in utero co-activation of LIN28A/CTNNB1, histological analysis of cortical lamination","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics observation in a complex genetic background without direct LAMB1 manipulation; preprint, single lab","pmids":["bio_10.1101_2024.08.01.606182"],"is_preprint":true}],"current_model":"LAMB1 encodes the beta-1 chain of laminin, a multidomain extracellular matrix glycoprotein with cysteine-rich repeats and helical domains that forms part of basement membranes; its expression is transcriptionally regulated by retinoic acid via PKA/cAMP-dependent enhancer elements and by the ERK/c-Jun axis, its mRNA stability is controlled by DDX24-nucleolin binding, and it functions mechanistically as a haptotactic signal (sensed by integrin alpha-6/Rac1) guiding retinal microglial migration, as a mechanosensory molecule coupling substrate stiffness to FAK-MEK1/2 signaling, and as an upstream activator of Wnt/β-catenin/VEGFA in endothelial angiogenesis and of NF-κB/HK2-driven glycolysis in glioma, while loss-of-function mutations cause cytosolic trapping of truncated protein and leukoencephalopathy, and dominant gain-of-function truncations appear to act through secretion of monomeric truncated forms."},"narrative":{"mechanistic_narrative":"LAMB1 encodes the laminin beta-1 chain, a large multidomain extracellular matrix glycoprotein built from cysteine-rich type A repeats, type B repeats, and globular and helical regions that contribute to basement membrane assembly [PMID:3611077]. Its transcription is induced by retinoic acid through a cAMP/PKA-dependent enhancer that activates a C2-binding protein [PMID:9419418] and is driven in cancer by an ERK/c-Jun axis in which c-Jun binds the LAMB1 promoter directly [PMID:33435161], while its mRNA is stabilized post-transcriptionally by DDX24 binding a defined site in cooperation with nucleolin [PMID:35763670]. As a secreted matrix protein, LAMB1 functions as an extracellular guidance and mechanotransduction cue: vascular LAMB1 forms a haptotactic gradient sensed by integrin alpha-6 to activate Rac1 and direct microglial precursor migration into the retina [PMID:41206867], and it binds focal adhesion kinase to convert substrate stiffness into MEK1/2 signaling [PMID:36519511]. In disease and tumor contexts LAMB1 acts upstream of multiple intracellular cascades, promoting Wnt/β-catenin/VEGFA-driven angiogenesis [PMID:40221061] and NF-κB/HK2-driven glycolysis in glioma [PMID:39920513]. A dominant missense mutation in mouse Lamb1 causes a dystonia-like movement disorder with abnormal cerebellar output [PMID:26705335], and human LAMB1 truncating variants cause leukoencephalopathy, acting either through cytosolic trapping of truncated protein [PMID:34606115] or, for late truncations, through secretion of a monomeric truncated form consistent with a gain-of-function mechanism [PMID:40237576].","teleology":[{"year":1987,"claim":"Established the molecular identity of LAMB1 by defining its multidomain architecture and chromosomal location, providing the foundation for all subsequent functional work.","evidence":"cDNA cloning, sequence analysis, and chromosomal mapping by somatic cell hybrid and in situ hybridization","pmids":["3611077"],"confidence":"High","gaps":["No functional assignment to individual domains","No structural model of assembled laminin"]},{"year":1997,"claim":"Resolved how LAMB1 transcription is induced developmentally, showing retinoic acid acts through a cAMP/PKA-dependent enhancer requiring a specific C2-binding factor.","evidence":"Dominant-negative PKA transfection, CAT reporter, DNase I hypersensitivity, and EMSA in F9 teratocarcinoma cells","pmids":["9419418"],"confidence":"Medium","gaps":["Identity of the C2-binding protein not determined","Generalizability beyond F9 cells unclear"]},{"year":1997,"claim":"Mapped the cis-regulatory elements controlling tissue-specific LAMB1 expression, separating a minimal proximal promoter from distal elements needed in reproductive epithelia.","evidence":"Transgenic mouse promoter-lacZ reporter lines with two promoter fragments","pmids":["9447707"],"confidence":"Medium","gaps":["Trans-acting factors at distal elements not identified","No link to protein function"]},{"year":2015,"claim":"Demonstrated a CNS role for LAMB1 beyond basement membranes, with a dominant missense mutation causing dystonia-like movement through abnormal cerebellar circuit output.","evidence":"Exome sequencing plus in vivo awake cerebellar electrophysiology and EMG in mutant mice","pmids":["26705335"],"confidence":"High","gaps":["Molecular consequence of the missense change on laminin assembly unknown","Synaptic mechanism not directly defined"]},{"year":2021,"claim":"Defined the cellular pathology of recessive LAMB1 leukoencephalopathy, showing truncated protein escaping NMD is trapped in the cytosol rather than secreted.","evidence":"Western blotting with N- and C-terminal antibodies in patient fibroblasts plus collapsing variant analysis","pmids":["34606115"],"confidence":"Medium","gaps":["Mechanism linking cytosolic trapping to neuropathology unresolved","Single-lab patient cell analysis"]},{"year":2021,"claim":"Placed LAMB1 downstream of oncogenic ERK signaling by showing c-Jun directly transactivates its promoter to drive gastric cancer growth.","evidence":"Overexpression/knockdown, ERK inhibitor, ChIP for c-Jun, and proliferation/invasion assays in gastric cancer cells","pmids":["33435161"],"confidence":"Medium","gaps":["Downstream effectors of LAMB1 in gastric cancer not defined","Single-lab study"]},{"year":2022,"claim":"Identified a post-transcriptional control mechanism, showing DDX24 binds a defined LAMB1 mRNA site and stabilizes it via nucleolin to promote HCC progression.","evidence":"RIP mapping, mRNA stability assay, DDX24-nucleolin Co-IP, and in vitro/in vivo tumor models","pmids":["35763670"],"confidence":"High","gaps":["Whether stabilization operates in non-tumor tissues unknown","Receptor/effector downstream of elevated LAMB1 protein not addressed"]},{"year":2023,"claim":"Established LAMB1 as a mechanotransducer, showing it binds FAK to convert substrate stiffness into MEK1/2 signaling during dentinogenesis.","evidence":"Co-immunoprecipitation, stiffness-variable PDMS substrates, and pathway Western blotting in odontoblast-like cells","pmids":["36519511"],"confidence":"Medium","gaps":["Direct vs indirect LAMB1-FAK interaction not distinguished","Single-lab, single cell type"]},{"year":2025,"claim":"Defined a conserved haptotactic guidance function, showing vascular LAMB1 engages integrin alpha-6 to activate Rac1 and direct microglial precursor migration into the retina.","evidence":"Zebrafish live imaging, endothelial-specific conditional KO in mice, F-actin polarization and Rac1 activity assays","pmids":["41206867"],"confidence":"High","gaps":["Structural basis of the LAMB1-Itga6 gradient not resolved","Other receptors contributing to migration not excluded"]},{"year":2025,"claim":"Distinguished the disease mechanism of late LAMB1 truncations, showing they uniquely secrete as monomers consistent with dominant gain-of-function, and confirmed a conserved BBB role.","evidence":"Drosophila LanB1 RNAi and rescue, immunofluorescence, and HEK293T variant secretion assays","pmids":["40237576"],"confidence":"Medium","gaps":["How secreted monomeric truncated protein produces toxicity unknown","Human in vivo validation lacking"]},{"year":2025,"claim":"Placed LAMB1 upstream of pro-angiogenic Wnt signaling, showing knockdown reduces Wnt/β-catenin/VEGFA and impairs endothelial tube formation, rescuable by a Wnt agonist.","evidence":"siRNA knockdown in HUVECs, Wnt agonist rescue, tube formation and migration assays, scRNA-seq pseudotime","pmids":["40221061"],"confidence":"Medium","gaps":["Receptor coupling LAMB1 to Wnt activation unidentified","Single-lab study"]},{"year":2025,"claim":"Linked LAMB1 to tumor metabolism, showing it drives NF-κB-dependent HK2 upregulation and glycolysis to support glioma growth and reduce TMZ sensitivity.","evidence":"Overexpression/knockdown, Seahorse ECAR, NF-κB inhibitor, and subcutaneous tumor model","pmids":["39920513"],"confidence":"Medium","gaps":["Mechanism by which LAMB1 activates NF-κB unknown","Single-lab study"]},{"year":2026,"claim":"Extended LAMB1 signaling to bone-muscle crosstalk, showing recombinant LAMB1 promotes osteoclastogenesis via p38/JNK MAPK activation.","evidence":"In vitro osteoclastogenesis with recombinant LAMB1, TRAP staining, MAPK Western blotting, dual-tissue transcriptomics in an OVX model","pmids":["41690031"],"confidence":"Medium","gaps":["Osteoclast receptor for LAMB1 not identified","Limited mechanistic detail beyond MAPK readout"]},{"year":2026,"claim":"Implicated LAMB1 in trophoblast function, showing silencing modulates the COL3A1/RAC1 axis to enhance invasion and improve outcomes in a subchorionic hematoma model.","evidence":"siRNA and in vivo knockdown, proteomic/transcriptomic analysis, SCH rat model, trophoblast functional assays","pmids":["41840580"],"confidence":"Medium","gaps":["Direct molecular link between LAMB1 and COL3A1/RAC1 not established","Single-lab study"]},{"year":null,"claim":"How LAMB1's matrix structural role integrates with its diverse intracellular signaling outputs (FAK/MEK, Rac1, Wnt, NF-κB, MAPK) through specific receptors across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["A unifying receptor logic for distinct downstream pathways is undefined","Structural model of LAMB1 within assembled laminin and basement membrane is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,7]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,2]}],"complexes":["laminin","basement membrane"],"partners":["ITGA6","FAK","DDX24","RPSA","ITGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07942","full_name":"Laminin subunit beta-1","aliases":["Laminin B1 chain","Laminin-1 subunit beta","Laminin-10 subunit beta","Laminin-12 subunit beta","Laminin-2 subunit beta","Laminin-6 subunit beta","Laminin-8 subunit beta"],"length_aa":1786,"mass_kda":198.0,"function":"Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Involved in the organization of the laminar architecture of the cerebral cortex (PubMed:23472759). It is probably required for the integrity of the basement membrane/glia limitans that serves as an anchor point for the endfeet of radial glial cells and as a physical barrier to migrating neurons (By similarity). Radial glial cells play a central role in cerebral cortical development, where they act both as the proliferative unit of the cerebral cortex and a scaffold for neurons migrating toward the pial surface (By similarity). As a subunit of laminin-1 (also known as laminin-111 or EHS laminin), it is involved in the stimulation of agrin-induced receptor clustering through a MuSK-independent pathway (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/P07942/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMB1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ALCAM","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LAMB1","total_profiled":1310},"omim":[{"mim_id":"621424","title":"LEUKOENCEPHALOPATHY WITHOUT LACUNAE, ADULT-ONSET; LUCAO","url":"https://www.omim.org/entry/621424"},{"mim_id":"615960","title":"PORETTI-BOLTSHAUSER SYNDROME; PTBHS","url":"https://www.omim.org/entry/615960"},{"mim_id":"615191","title":"LEUKOENCEPHALOPATHY WITH VARIABLE CORTICAL BRAIN MALFORMATIONS AND/OR HYDROCEPHALUS; LKBMH","url":"https://www.omim.org/entry/615191"},{"mim_id":"609915","title":"CARDIOMYOPATHY, DILATED, 1Q; CMD1Q","url":"https://www.omim.org/entry/609915"},{"mim_id":"607432","title":"LISSENCEPHALY 1; LIS1","url":"https://www.omim.org/entry/607432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":145.0}],"url":"https://www.proteinatlas.org/search/LAMB1"},"hgnc":{"alias_symbol":[],"prev_symbol":["CLM"]},"alphafold":{"accession":"P07942","domains":[{"cath_id":"2.60.120.260","chopping":"47-273","consensus_level":"high","plddt":85.8477,"start":47,"end":273},{"cath_id":"2.60.120.260","chopping":"556-636_650-709","consensus_level":"medium","plddt":85.7815,"start":556,"end":709},{"cath_id":"2.10.25.10","chopping":"982-1028","consensus_level":"medium","plddt":81.127,"start":982,"end":1028},{"cath_id":"-","chopping":"1254-1283_1655-1692","consensus_level":"medium","plddt":70.2281,"start":1254,"end":1692},{"cath_id":"1.20.5","chopping":"1751-1786","consensus_level":"medium","plddt":71.3672,"start":1751,"end":1786}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07942","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07942-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07942-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAMB1","jax_strain_url":"https://www.jax.org/strain/search?query=LAMB1"},"sequence":{"accession":"P07942","fasta_url":"https://rest.uniprot.org/uniprotkb/P07942.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07942/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07942"}},"corpus_meta":[{"pmid":"3611077","id":"PMC_3611077","title":"Human laminin B1 chain. A multidomain protein with gene (LAMB1) locus in the q22 region of chromosome 7.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3611077","citation_count":174,"is_preprint":false},{"pmid":"18809619","id":"PMC_18809619","title":"Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18809619","citation_count":56,"is_preprint":false},{"pmid":"33435161","id":"PMC_33435161","title":"Upregulation of LAMB1 via ERK/c-Jun Axis Promotes Gastric Cancer Growth and Motility.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33435161","citation_count":45,"is_preprint":false},{"pmid":"24497408","id":"PMC_24497408","title":"MiR-124-5p inhibits the growth of high-grade gliomas through posttranscriptional 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The LAMB1 gene was mapped to chromosome 7q22 by somatic cell hybrid methodology and in situ hybridization.\",\n      \"method\": \"cDNA cloning, sequence analysis, somatic cell hybrid methodology, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete cDNA sequence with domain architecture established by direct molecular cloning and chromosomal mapping; foundational characterization replicated in subsequent work\",\n      \"pmids\": [\"3611077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The LAMB1 gene is regulated by retinoic acid (RA) and cAMP/PKA signaling. In F9 teratocarcinoma cells partially deficient in PKA activity, cAMP-associated activation of the LAMB1 DNase I hypersensitivity site 2 enhancer was significantly decreased. EMSA showed reduced protein binding at the C2 motif within this enhancer in PKA-deficient cells after RA+cAMP treatment, and in vitro phosphorylation failed to rescue C2 binding, indicating PKA is required for induction of the C2-binding protein.\",\n      \"method\": \"Stable transfection of dominant-negative PKA regulatory subunit, chloramphenicol acetyltransferase (CAT) assay, DNase I hypersensitivity, electrophoretic mobility shift assay (EMSA), in vitro phosphorylation\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CAT assay, DNase I hypersensitivity, EMSA) in a single lab establishing PKA involvement in LAMB1 enhancer activation\",\n      \"pmids\": [\"9419418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The first 0.7 kb of LAMB1 5' flanking sequence is sufficient to direct expression in prospermatogonia cells of the testis, while additional elements within 4 kb 5' of the transcription start site are required for expression in oocytes and epithelial cells of mesonephric ducts, ductus deferens, ductus epididymis, and seminal vesicles.\",\n      \"method\": \"Transgenic mouse lines with LAMB1 promoter fragments fused to lacZ reporter gene; beta-galactosidase staining\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo promoter dissection using transgenic mice with two different promoter-reporter constructs, single lab\",\n      \"pmids\": [\"9447707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A dominant missense mutation in mouse Lamb1 (lamb1t) causes a dystonia-like movement disorder. Cerebellar recordings in awake mice detected abnormal output from Purkinje cells and their deep cerebellar nucleus targets during abnormal postures, implicating Lamb1 in synapse structure/plasticity in CNS circuits that regulate movement. The phenotype depends on interaction of brain and spinal cord circuits.\",\n      \"method\": \"SNP mapping, exome sequencing, in vivo electrophysiology (awake cerebellar recordings), electromyography showing co-contraction of opposing muscle groups\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — causative mutation identified by exome sequencing, phenotype characterized by multiple orthogonal methods (EMG, awake neural recording), published in peer-reviewed journal\",\n      \"pmids\": [\"26705335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LAMB1 truncating variants that escape nonsense-mediated mRNA decay produce truncated LAMB1 proteins that are trapped in the cytosol rather than being secreted to the extracellular matrix, as demonstrated using two antibodies recognizing N- and C-terminal parts of LAMB1 in endogenous patient fibroblasts. These variants cause a leukoencephalopathy with hippocampal memory defects.\",\n      \"method\": \"Western blotting with N- and C-terminal antibodies, gene-based collapsing test of rare protein-truncating variants in exome data, patient fibroblast analysis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization experiment in patient-derived cells using two orthogonal antibodies, single lab\",\n      \"pmids\": [\"34606115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LAMB1 promotes gastric cancer cell growth and motility. The ERK inhibitor U0126 reduces LAMB1 expression, and c-Jun was shown to directly bind the LAMB1 promoter and regulate its transcription via the ERK pathway.\",\n      \"method\": \"LAMB1 overexpression and knockdown in gastric cancer cells, ERK inhibitor treatment, chromatin immunoprecipitation (c-Jun binding to LAMB1 promoter), cell proliferation/invasion/migration assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP combined with loss-of-function and pharmacological inhibition, single lab\",\n      \"pmids\": [\"33435161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX24 binds the mRNA of LAMB1 at nucleotides 618-624 and increases LAMB1 mRNA stability in a manner dependent on the interaction between nucleolin and the C-terminal region of DDX24, thereby promoting HCC cell migration and proliferation.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, DDX24 overexpression/knockdown, Co-IP (DDX24-nucleolin interaction), in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct RNA-binding site identified by RIP, mRNA stability measured, protein interaction by Co-IP, functional rescue experiments in vitro and in vivo in a single rigorous study\",\n      \"pmids\": [\"35763670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAMB1 binds FAK (focal adhesion kinase) and this interaction converts mechanical substrate stiffness signals into biochemical signaling that controls MEK1/2 activity during dentinogenesis in odontoblast-like cells.\",\n      \"method\": \"Immunoprecipitation (LAMB1-FAK interaction), immunofluorescent staining, Western blotting, polydimethylsiloxane substrates of varying stiffness, qPCR\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct LAMB1-FAK interaction shown by immunoprecipitation with functional downstream pathway (MEK1/2) readout, single lab\",\n      \"pmids\": [\"36519511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Vascular LAMB1 provides a haptotactic gradient sensed by Itga6 (integrin alpha-6) on retinal microglial precursors. Lamb1-Itga6 engagement activates Rac1 signaling, promoting F-actin polarization and directional migration of microglial precursors into the developing retina via blood vessels. Endothelial-specific LAMB1 deficiency in mice impairs microglial precursor settlement.\",\n      \"method\": \"Zebrafish live imaging, genetic interference with Lamb1/Itga6 axis, endothelial-specific conditional knockout in mice, F-actin polarization assay, Rac1 activity assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conserved mechanism validated in two organisms (zebrafish and mouse) with multiple orthogonal methods including conditional KO, live imaging, and signaling readouts\",\n      \"pmids\": [\"41206867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, the LAMB1 ortholog LanB1 localizes to the blood-brain barrier (BBB) in adult fly brains and is expressed in a subset of glial cells. Knockdown of LanB1 in the BBB results in short lifespan and locomotor defects. In vitro assay in HEK293T cells showed that late-truncated LAMB1 is uniquely detected as a monomer in culture medium (unlike full-length or early frameshift variants), suggesting dominant leukoencephalopathy variants act through a gain-of-function mechanism via secretion of truncated monomeric protein.\",\n      \"method\": \"Drosophila LanB1 knockdown (RNAi), immunofluorescence localization, in vivo overexpression/rescue experiments with variant alleles, HEK293T cell expression assay with Western blotting\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vivo Drosophila genetics, in vitro human cell assay) in a single study establishing BBB localization and gain-of-function mechanism for truncation variants\",\n      \"pmids\": [\"40237576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LAMB1 promotes glioma cell glycolysis and proliferation via activation of the NF-κB pathway, which upregulates hexokinase 2 (HK2). Inhibition of NF-κB by Bay 11-7082 phenocopied LAMB1 knockdown in suppressing glycolysis (measured by ECAR) and tumor growth, and reducing TMZ sensitivity.\",\n      \"method\": \"LAMB1 overexpression/knockdown in glioma cells, Seahorse ECAR measurement, NF-κB pathway inhibitor (Bay 11-7082), Western blotting for HK2/NF-κB components, subcutaneous tumor model\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by pharmacological inhibitor combined with loss/gain-of-function and metabolic readouts, single lab\",\n      \"pmids\": [\"39920513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LAMB1 knockdown suppresses Wnt/β-catenin signaling in endothelial cells, reducing expression of wnt3a, GSK-3β, β-catenin, and VEGFA, and impairing HUVEC proliferation, migration, and tube formation. The Wnt agonist HY-141873 partially rescued these defects, placing LAMB1 upstream of Wnt/β-catenin/VEGFA in angiogenesis during fracture healing.\",\n      \"method\": \"siRNA-mediated LAMB1 knockdown in HUVECs, Western blotting, Wnt agonist rescue experiment, tube formation assay, transwell migration assay, scRNA-seq pseudotime analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by pharmacological rescue of KD phenotype, multiple functional readouts, single lab\",\n      \"pmids\": [\"40221061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Recombinant LAMB1 protein (rLAMB1) promotes osteoclast formation by activating the MAPK signaling pathway (phosphorylation of p38 and JNK). Muscle-secreted LAMB1 and CTGF were upregulated in bone in an OVX osteoporosis model and mediated bone-muscle crosstalk through MAPK activation.\",\n      \"method\": \"In vitro osteoclastogenesis assay with recombinant LAMB1, TRAP staining, Western blotting for MAPK phosphorylation, dual-tissue transcriptomics, protein-peptide docking\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — recombinant protein in vitro assay with MAPK readout, but single lab and limited mechanistic detail on receptor\",\n      \"pmids\": [\"41690031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LAMB1 silencing in trophoblast (HTR-8/SVneo) cells modulates the COL3A1/RAC1 axis: LAMB1 knockdown reduced pro-inflammatory cytokine levels, enhanced trophoblast proliferation/migration/invasion, and improved pregnancy outcomes in an LPS-induced SCH rat model. LAMB1 expression was positively correlated with COL3A1 and inversely with RAC1 in SCH tissues.\",\n      \"method\": \"LAMB1 knockdown (siRNA/in vivo), proteomic and transcriptomic analysis, in vivo SCH rat model, trophoblast functional assays (proliferation, migration, invasion), cytokine measurement\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined molecular and functional readouts, single lab\",\n      \"pmids\": [\"41840580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a cortical migration disorder model (co-activation of LIN28A and CTNNB1), spatially resolved proteome analysis revealed imbalances of extracellular matrix protein LAMB1 and its receptors RPSA and ITGB1, accompanied by a porous pial border and overmigration of neural cells, suggesting LAMB1 and its receptors are required for pial border integrity and cortical neuronal migration.\",\n      \"method\": \"Spatially resolved proteomics, mouse in utero co-activation of LIN28A/CTNNB1, histological analysis of cortical lamination\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics observation in a complex genetic background without direct LAMB1 manipulation; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.08.01.606182\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LAMB1 encodes the beta-1 chain of laminin, a multidomain extracellular matrix glycoprotein with cysteine-rich repeats and helical domains that forms part of basement membranes; its expression is transcriptionally regulated by retinoic acid via PKA/cAMP-dependent enhancer elements and by the ERK/c-Jun axis, its mRNA stability is controlled by DDX24-nucleolin binding, and it functions mechanistically as a haptotactic signal (sensed by integrin alpha-6/Rac1) guiding retinal microglial migration, as a mechanosensory molecule coupling substrate stiffness to FAK-MEK1/2 signaling, and as an upstream activator of Wnt/β-catenin/VEGFA in endothelial angiogenesis and of NF-κB/HK2-driven glycolysis in glioma, while loss-of-function mutations cause cytosolic trapping of truncated protein and leukoencephalopathy, and dominant gain-of-function truncations appear to act through secretion of monomeric truncated forms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAMB1 encodes the laminin beta-1 chain, a large multidomain extracellular matrix glycoprotein built from cysteine-rich type A repeats, type B repeats, and globular and helical regions that contribute to basement membrane assembly [#0]. Its transcription is induced by retinoic acid through a cAMP/PKA-dependent enhancer that activates a C2-binding protein [#1] and is driven in cancer by an ERK/c-Jun axis in which c-Jun binds the LAMB1 promoter directly [#5], while its mRNA is stabilized post-transcriptionally by DDX24 binding a defined site in cooperation with nucleolin [#6]. As a secreted matrix protein, LAMB1 functions as an extracellular guidance and mechanotransduction cue: vascular LAMB1 forms a haptotactic gradient sensed by integrin alpha-6 to activate Rac1 and direct microglial precursor migration into the retina [#8], and it binds focal adhesion kinase to convert substrate stiffness into MEK1/2 signaling [#7]. In disease and tumor contexts LAMB1 acts upstream of multiple intracellular cascades, promoting Wnt/\\u03b2-catenin/VEGFA-driven angiogenesis [#11] and NF-\\u03baB/HK2-driven glycolysis in glioma [#10]. A dominant missense mutation in mouse Lamb1 causes a dystonia-like movement disorder with abnormal cerebellar output [#3], and human LAMB1 truncating variants cause leukoencephalopathy, acting either through cytosolic trapping of truncated protein [#4] or, for late truncations, through secretion of a monomeric truncated form consistent with a gain-of-function mechanism [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Established the molecular identity of LAMB1 by defining its multidomain architecture and chromosomal location, providing the foundation for all subsequent functional work.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and chromosomal mapping by somatic cell hybrid and in situ hybridization\",\n      \"pmids\": [\"3611077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assignment to individual domains\", \"No structural model of assembled laminin\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved how LAMB1 transcription is induced developmentally, showing retinoic acid acts through a cAMP/PKA-dependent enhancer requiring a specific C2-binding factor.\",\n      \"evidence\": \"Dominant-negative PKA transfection, CAT reporter, DNase I hypersensitivity, and EMSA in F9 teratocarcinoma cells\",\n      \"pmids\": [\"9419418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the C2-binding protein not determined\", \"Generalizability beyond F9 cells unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped the cis-regulatory elements controlling tissue-specific LAMB1 expression, separating a minimal proximal promoter from distal elements needed in reproductive epithelia.\",\n      \"evidence\": \"Transgenic mouse promoter-lacZ reporter lines with two promoter fragments\",\n      \"pmids\": [\"9447707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors at distal elements not identified\", \"No link to protein function\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a CNS role for LAMB1 beyond basement membranes, with a dominant missense mutation causing dystonia-like movement through abnormal cerebellar circuit output.\",\n      \"evidence\": \"Exome sequencing plus in vivo awake cerebellar electrophysiology and EMG in mutant mice\",\n      \"pmids\": [\"26705335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular consequence of the missense change on laminin assembly unknown\", \"Synaptic mechanism not directly defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the cellular pathology of recessive LAMB1 leukoencephalopathy, showing truncated protein escaping NMD is trapped in the cytosol rather than secreted.\",\n      \"evidence\": \"Western blotting with N- and C-terminal antibodies in patient fibroblasts plus collapsing variant analysis\",\n      \"pmids\": [\"34606115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking cytosolic trapping to neuropathology unresolved\", \"Single-lab patient cell analysis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed LAMB1 downstream of oncogenic ERK signaling by showing c-Jun directly transactivates its promoter to drive gastric cancer growth.\",\n      \"evidence\": \"Overexpression/knockdown, ERK inhibitor, ChIP for c-Jun, and proliferation/invasion assays in gastric cancer cells\",\n      \"pmids\": [\"33435161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of LAMB1 in gastric cancer not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a post-transcriptional control mechanism, showing DDX24 binds a defined LAMB1 mRNA site and stabilizes it via nucleolin to promote HCC progression.\",\n      \"evidence\": \"RIP mapping, mRNA stability assay, DDX24-nucleolin Co-IP, and in vitro/in vivo tumor models\",\n      \"pmids\": [\"35763670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilization operates in non-tumor tissues unknown\", \"Receptor/effector downstream of elevated LAMB1 protein not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established LAMB1 as a mechanotransducer, showing it binds FAK to convert substrate stiffness into MEK1/2 signaling during dentinogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation, stiffness-variable PDMS substrates, and pathway Western blotting in odontoblast-like cells\",\n      \"pmids\": [\"36519511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect LAMB1-FAK interaction not distinguished\", \"Single-lab, single cell type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a conserved haptotactic guidance function, showing vascular LAMB1 engages integrin alpha-6 to activate Rac1 and direct microglial precursor migration into the retina.\",\n      \"evidence\": \"Zebrafish live imaging, endothelial-specific conditional KO in mice, F-actin polarization and Rac1 activity assays\",\n      \"pmids\": [\"41206867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LAMB1-Itga6 gradient not resolved\", \"Other receptors contributing to migration not excluded\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished the disease mechanism of late LAMB1 truncations, showing they uniquely secrete as monomers consistent with dominant gain-of-function, and confirmed a conserved BBB role.\",\n      \"evidence\": \"Drosophila LanB1 RNAi and rescue, immunofluorescence, and HEK293T variant secretion assays\",\n      \"pmids\": [\"40237576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How secreted monomeric truncated protein produces toxicity unknown\", \"Human in vivo validation lacking\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed LAMB1 upstream of pro-angiogenic Wnt signaling, showing knockdown reduces Wnt/\\u03b2-catenin/VEGFA and impairs endothelial tube formation, rescuable by a Wnt agonist.\",\n      \"evidence\": \"siRNA knockdown in HUVECs, Wnt agonist rescue, tube formation and migration assays, scRNA-seq pseudotime\",\n      \"pmids\": [\"40221061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling LAMB1 to Wnt activation unidentified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked LAMB1 to tumor metabolism, showing it drives NF-\\u03baB-dependent HK2 upregulation and glycolysis to support glioma growth and reduce TMZ sensitivity.\",\n      \"evidence\": \"Overexpression/knockdown, Seahorse ECAR, NF-\\u03baB inhibitor, and subcutaneous tumor model\",\n      \"pmids\": [\"39920513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LAMB1 activates NF-\\u03baB unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended LAMB1 signaling to bone-muscle crosstalk, showing recombinant LAMB1 promotes osteoclastogenesis via p38/JNK MAPK activation.\",\n      \"evidence\": \"In vitro osteoclastogenesis with recombinant LAMB1, TRAP staining, MAPK Western blotting, dual-tissue transcriptomics in an OVX model\",\n      \"pmids\": [\"41690031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Osteoclast receptor for LAMB1 not identified\", \"Limited mechanistic detail beyond MAPK readout\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated LAMB1 in trophoblast function, showing silencing modulates the COL3A1/RAC1 axis to enhance invasion and improve outcomes in a subchorionic hematoma model.\",\n      \"evidence\": \"siRNA and in vivo knockdown, proteomic/transcriptomic analysis, SCH rat model, trophoblast functional assays\",\n      \"pmids\": [\"41840580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between LAMB1 and COL3A1/RAC1 not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LAMB1's matrix structural role integrates with its diverse intracellular signaling outputs (FAK/MEK, Rac1, Wnt, NF-\\u03baB, MAPK) through specific receptors across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"A unifying receptor logic for distinct downstream pathways is undefined\", \"Structural model of LAMB1 within assembled laminin and basement membrane is lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 2]}\n    ],\n    \"complexes\": [\"laminin\", \"basement membrane\"],\n    \"partners\": [\"ITGA6\", \"FAK\", \"DDX24\", \"RPSA\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}