{"gene":"SPTAN1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2017,"finding":"SPTAN1 mutations within the α/β spectrin heterodimerization domain (specifically the amino acid stretch Asp2303 to Met2309 in the α20 repeat) cause αII/βII spectrin aggregate formation and accumulation of αII spectrin in the insoluble protein fraction, as demonstrated in patient-derived fibroblasts. Mutations outside this domain do not produce aggregates and are associated with milder phenotypes.","method":"Triton-X extraction (biochemical fractionation) and immunocytochemistry with fluorescence microscopy on patient fibroblasts; molecular modelling of mutant spectrin repeats","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and imaging in patient-derived cells, two orthogonal methods, single lab","pmids":["29050398"],"is_preprint":false},{"year":2015,"finding":"In-frame mutations in the last two spectrin repeats (C-terminal region) of SPTAN1, which constitute the nucleation site for α/β spectrin heterodimer formation, exert dominant negative effects by altering heterodimer formation between αII and βII spectrin, leading to epileptic encephalopathy.","method":"Review and synthesis of patient genetic data combined with functional inference from aggregate formation studies in transfected cells (referenced from prior work)","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replicated across multiple patient reports and cell-based observations, but primarily synthesis/review; mechanism inferred from cellular aggregation data","pmids":["25631096"],"is_preprint":false},{"year":2012,"finding":"De novo in-frame SPTAN1 mutations (p.E2207del and p.R2308_M2309dup, and p.Q2202del) in the C-terminal domain induce different patterns of spectrin subunit aggregation in transfected neuronal cell lines, establishing that distinct mutations at this domain cause different aggregation phenotypes.","method":"Transfection of neuronal cell lines with mutant SPTAN1 constructs; immunocytochemistry to assess spectrin aggregation patterns","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-based functional assay in neuronal lines with defined mutations, single lab, two mutations compared","pmids":["22258530"],"is_preprint":false},{"year":2016,"finding":"SPTAN1 (αII spectrin) is a component of the αII Sp/FANCA/XPF DNA repair complex; miR-128-3p targets SPTAN1 to reduce its protein level via translational inhibition, thereby attenuating repair of DNA inter-strand crosslinks (ICLs), inducing cell cycle arrest and chromosomal instability in lung cancer cells treated with mitomycin C.","method":"Computational prediction and experimental validation (luciferase reporter/miRNA target assay); Western blot for protein level; co-immunoprecipitation for αII Sp/FANCA/XPF complex; cell cycle analysis; chromosomal aberration assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, knockdown, cell cycle assay), single lab","pmids":["28938540"],"is_preprint":false},{"year":2014,"finding":"SPTAN1 physically interacts with MLH1 (mismatch repair protein) and regulates cellular migration; overexpression of SPTAN1 increases migration of MLH1-deficient cells, while siRNA knockdown of SPTAN1 decreases migration of MLH1-proficient cells, establishing a SPTAN1-dependent migration function.","method":"siRNA knockdown of SPTAN1 and MLH1; SPTAN1 overexpression; cellular motility assays in multiple cancer cell lines","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with defined phenotypic readout (migration), single lab, multiple cell lines","pmids":["24456667"],"is_preprint":false},{"year":2019,"finding":"SPTAN1 knockdown in colon cancer cell lines decreases cell viability, impairs cellular mobility, and reduces cell-cell contact formation, indicating roles in cell growth, motility, and adhesion.","method":"siRNA knockdown of SPTAN1 in CRC cell lines; cell viability assays; migration assays; microscopy for cell-cell contacts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple defined phenotypic readouts, single lab","pmids":["30856214"],"is_preprint":false},{"year":2023,"finding":"SPTAN1 acts as a cell density sensor upstream of Hippo signaling: at high cell density, SPTAN1 is phosphorylated, recruits NUMB1/2 to the plasma membrane, which sequesters MARK kinases at the membrane preventing their inhibition of MST1/2, enhancing WW45-MST1/2 interaction, activating Hippo signaling and suppressing YAP. At low density, SPTAN1 is dephosphorylated, NUMB moves to cytoplasm, MARKs inhibit MST1/2, and YAP is activated. NUMB isoforms 3/4 (truncated PTB domain) cannot interact with phospho-SPTAN1 and are upregulated in liver cancer.","method":"Co-immunoprecipitation (SPTAN1-NUMB interaction); phosphorylation studies; NUMB isoform knockdown/overexpression; MST1/2 kinase activity assays; double KO (NUMB/WW45) mouse liver model; YAP activity readout; liver organomegaly and tumorigenesis assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, KO mouse model, kinase assays, cell density experiments), mechanistic pathway placement established with in vivo validation","pmids":["37843276"],"is_preprint":false},{"year":2021,"finding":"Hair cell-specific knockout of Sptan1 in mice causes rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of hair cells from cochlear middle and apical turns. Sptan1 deficiency leads to decreased cell spreading, abnormal focal adhesion formation, and impaired integrin signaling in hair cells.","method":"Hair cell-specific Sptan1 conditional knockout mouse; auditory brainstem response testing; electron and fluorescence microscopy of stereocilia/cuticular plate morphology; focal adhesion and integrin signaling analysis in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (auditory function, morphology, signaling), rigorous in vivo and in vitro methods","pmids":["34708331"],"is_preprint":false},{"year":2025,"finding":"SPTAN1 undergoes lactylation (at K1952 and K1957) in HBV-positive hepatocellular carcinoma tissue. AARS1 (alanyl-tRNA synthetase 1) mediates SPTAN1 lactylation, while HDAC1 acts as a delactylase. HBV infection induces HK2-driven lactate production, promoting SPTAN1 lactylation, which disrupts cytoplasmic SPTAN1 liquid-liquid phase separation and facilitates nuclear translocation. In the nucleus, lactylated SPTAN1 interacts with CBFB to activate NOTCH1/HES1 signaling, promoting HCC proliferation and immunosuppression via COX2/mPGES1/PGE2 pathway.","method":"Mass spectrometry for lactylation site identification; AARS1/HDAC1 overexpression and knockdown; Co-immunoprecipitation (SPTAN1-CBFB); live-cell imaging for LLPS and nuclear translocation; NOTCH1/HES1 reporter assays; preclinical tumor models with inhibitory peptides","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including MS, co-IP, and in vivo models, single lab, novel PTM with writer/eraser identified","pmids":["41243220"],"is_preprint":false},{"year":2026,"finding":"Reduced SPTAN1 levels are a key regulator of RAC1 activation and cystic pathology in ARPKD models; SPTAN1-mutant kidney organoids and mice exhibit distal-nephron cysts with elevated RAC1/c-FOS expression and altered calcium signaling. Restoring SPTAN1 in PKHD1-/- organoids via CRISPR activation alleviates cystic phenotypes, normalizes intracellular calcium, and reduces RAC1/c-FOS expression.","method":"Kidney organoid-on-chip models; transgenic mice; CRISPR activation (CRISPRa) for SPTAN1 restoration; transcriptomics and single-cell RNA-seq; live calcium imaging; immunostaining for RAC1/c-FOS","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal models (organoids, mice, patient samples), gain-of-function rescue with defined molecular readouts, single lab","pmids":["41742835"],"is_preprint":false},{"year":2025,"finding":"Loss-of-function variants in SPTAN1 (frameshift, nonsense, splice-site) in muscle cause distal myopathy with nonsense-mediated decay of SPTAN1 mRNA confirmed in patient-derived muscle tissue. Protein expression was reduced concordantly in affected patients.","method":"qPCR and Western blotting on patient-derived muscle tissue; mRNA expression analysis and cDNA sequencing; muscle biopsy histopathology; electrophysiology; muscle MRI/CT","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular analysis of patient tissue with NMD confirmation, multiple families, multi-center collaboration","pmids":["40023774"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, the SPTAN1 variant p.(Gln1448Pro) reduces protein abundance and impairs SPTAN1 localization to axons, and fails to restore voltage-gated sodium channel localization in sptan1-null axons, establishing a role for SPTAN1 in anchoring voltage-gated sodium channels at axons.","method":"Ectopic expression of wild-type and variant sptan1 in zebrafish; immunofluorescence for SPTAN1 and voltage-gated sodium channel localization in axons; behavioral motility assays; protein abundance quantification","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue/complementation experiment in zebrafish with defined molecular readout (NaV channel localization), single lab","pmids":["39988451"],"is_preprint":false},{"year":2024,"finding":"Loss of αII-spectrin (Sptan1) in mouse epidermis alters cell shape in all layers and impairs epidermal differentiation and barrier formation. αII-spectrin organizes the keratinocyte actomyosin cortex, and E-cadherin guides differential gradients of actin and spectrin to regulate layer-specific sub-membraneous spectrin-actomyosin network organization. This organization is required to dissipate tension, maintain structural integrity, and retain active EGFR and TRPV3 at the membrane in upper layers to induce terminal differentiation.","method":"Conditional Sptan1 knockout in mouse epidermis; high-resolution imaging; laser ablation (cortical tension); immunofluorescence for EGFR and TRPV3 membrane retention; barrier function assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, laser ablation, imaging), in vivo model, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2022,"finding":"Irregular αII-spectrin aggregation was observed in fibroblasts from patients carrying SPTAN1 variants p.(Arg19Trp) and p.(Glu2207del), extending the aggregation phenotype beyond the C-terminal heterodimerization domain to include N-terminal variants.","method":"Immunocytochemistry and fluorescence microscopy on patient-derived fibroblasts","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (immunocytochemistry), single lab, limited functional follow-up","pmids":["36331550"],"is_preprint":false},{"year":2024,"finding":"Low SPTAN1 expression is associated with enhanced ERK phosphorylation (via RAS-mediated RAF/MEK/ERK pathway activation) and increased IL-8 secretion in CRC cell lines with stable SPTAN1 knockdown, and ERK inhibition reduces IL-8 secretion in these cells.","method":"Stable SPTAN1 knockdown cell lines (SW480, SW620, HT-29); Western blot for ERK phosphorylation; IL-8 ELISA; pharmacological ERK inhibition (U0126)","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with defined signaling readout, but indirect pathway placement, single lab, limited mechanistic depth","pmids":["38891846"],"is_preprint":false}],"current_model":"SPTAN1 (αII-spectrin/α-fodrin) is a plasma membrane-stabilizing cytoskeletal scaffolding protein that forms obligate αII/βII spectrin heterodimers via its C-terminal nucleation domain; in-frame mutations in this domain disrupt heterodimer formation and cause pathological protein aggregation. It functions as a cell density sensor by undergoing phosphorylation at high density to recruit NUMB1/2 to the plasma membrane, sequestering MARK kinases and thereby activating Hippo/MST1/2 signaling to suppress YAP-driven proliferation. SPTAN1 anchors voltage-gated sodium channels at axons, participates in a FANCA/XPF DNA repair complex at inter-strand crosslinks, organizes the sub-membraneous actomyosin cortex to regulate cell shape and EGFR/TRPV3 membrane retention in keratinocyte differentiation, supports focal adhesion/integrin signaling in cochlear hair cells, regulates cellular migration downstream of MLH1, and can undergo oncogenic lactylation (at K1952/K1957, mediated by AARS1 and reversed by HDAC1) that drives nuclear translocation and CBFB-mediated NOTCH1/HES1 activation in hepatocellular carcinoma."},"narrative":{"mechanistic_narrative":"SPTAN1 (αII-spectrin/α-fodrin) is a sub-membraneous cytoskeletal scaffolding protein that forms obligate αII/βII spectrin heterodimers through a C-terminal nucleation domain in its last spectrin repeats, organizing the cortical actomyosin network that maintains cell shape, tissue integrity, and membrane protein anchoring [PMID:25631096]. In-frame mutations within this heterodimerization domain act dominant-negatively, disrupting heterodimer assembly and driving αII/βII spectrin into insoluble aggregates, the molecular lesion underlying SPTAN1-related epileptic encephalopathy [PMID:29050398, PMID:25631096, PMID:22258530]. Through this cortical scaffolding role, SPTAN1 anchors voltage-gated sodium channels at axons [PMID:39988451], supports focal adhesion and integrin signaling required for cochlear hair cell stereocilia and cuticular plate formation [PMID:34708331], and retains active EGFR and TRPV3 at the keratinocyte membrane to drive epidermal terminal differentiation and barrier formation. Beyond structural scaffolding, SPTAN1 functions as a cell density sensor upstream of Hippo signaling: at high density it is phosphorylated and recruits NUMB1/2 to the plasma membrane, sequestering MARK kinases to relieve their inhibition of MST1/2 and thereby suppressing YAP-driven proliferation [PMID:37843276]. SPTAN1 additionally participates in DNA inter-strand crosslink repair as a component of an αII-spectrin/FANCA/XPF complex [PMID:28938540], physically interacts with MLH1 to regulate cell migration [PMID:24456667], and supports cancer cell viability, motility, and cell-cell contact [PMID:30856214]. Loss-of-function variants causing nonsense-mediated decay produce a distal myopathy [PMID:40023774], and reduced SPTAN1 drives RAC1/c-FOS activation and cystic pathology in ARPKD kidney models [PMID:41742835]. In hepatocellular carcinoma, AARS1-mediated lactylation at K1952/K1957 (reversed by HDAC1) disrupts cytoplasmic SPTAN1 phase separation, promoting nuclear translocation and CBFB-dependent NOTCH1/HES1 activation [PMID:41243220].","teleology":[{"year":2012,"claim":"Established that distinct de novo in-frame mutations in the SPTAN1 C-terminal domain produce different spectrin aggregation phenotypes, linking specific lesions to molecular pathology.","evidence":"Transfection of mutant SPTAN1 into neuronal cell lines with immunocytochemistry of aggregation patterns","pmids":["22258530"],"confidence":"Medium","gaps":["Did not establish how aggregation translates to neuronal dysfunction","No quantification of heterodimer disruption per mutation"]},{"year":2014,"claim":"Identified a physical SPTAN1-MLH1 interaction and a SPTAN1-dependent migration function, extending SPTAN1 beyond a purely structural role into mismatch-repair-linked motility control.","evidence":"siRNA knockdown, overexpression, and motility assays across multiple cancer cell lines","pmids":["24456667"],"confidence":"Medium","gaps":["Interaction not mapped to specific domains","Mechanism linking MLH1 status to migration unresolved"]},{"year":2015,"claim":"Synthesized patient and cell data to define the C-terminal nucleation site as the heterodimerization hotspot whose mutation exerts dominant-negative effects in epileptic encephalopathy.","evidence":"Review and synthesis of patient genetics with cell-based aggregation inference","pmids":["25631096"],"confidence":"Medium","gaps":["Primarily synthesis rather than new experiment","Genotype-phenotype mapping incomplete"]},{"year":2016,"claim":"Placed SPTAN1 within an αII-spectrin/FANCA/XPF DNA repair complex and showed miR-128-3p suppression of SPTAN1 attenuates inter-strand crosslink repair, defining a genome-maintenance role.","evidence":"Co-IP, luciferase miRNA target assay, Western blot, cell cycle and chromosomal aberration assays in lung cancer cells","pmids":["28938540"],"confidence":"Medium","gaps":["Direct structural role of SPTAN1 in repair not defined","Single lung cancer context"]},{"year":2017,"claim":"Localized the pathogenic aggregation defect to the Asp2303-Met2309 stretch of the α20 repeat, demonstrating that only heterodimerization-domain mutations drive insoluble αII spectrin accumulation.","evidence":"Triton-X biochemical fractionation, immunocytochemistry on patient fibroblasts, and molecular modelling","pmids":["29050398"],"confidence":"Medium","gaps":["Did not establish how insoluble aggregates impair neuronal function","Single lab"]},{"year":2019,"claim":"Demonstrated that SPTAN1 supports colon cancer cell viability, motility, and cell-cell contact formation, generalizing its role in cell adhesion and growth.","evidence":"siRNA knockdown with viability, migration, and microscopy readouts in CRC lines","pmids":["30856214"],"confidence":"Medium","gaps":["Molecular effectors downstream not identified","Phenotypes correlative"]},{"year":2021,"claim":"Showed via hair cell conditional knockout that SPTAN1 is required for stereocilia/cuticular plate formation and hearing through focal adhesion and integrin signaling, defining a tissue-specific cytoskeletal role.","evidence":"Hair cell-specific Sptan1 conditional KO mouse, ABR testing, EM/fluorescence morphology, integrin signaling analysis in HEI-OC1 cells","pmids":["34708331"],"confidence":"High","gaps":["Direct integrin-spectrin biochemical linkage not resolved","Relevance to human deafness inferred"]},{"year":2023,"claim":"Defined SPTAN1 as a phosphorylation-dependent cell density sensor that recruits NUMB1/2 to sequester MARK kinases and activate Hippo/MST1/2 signaling, suppressing YAP proliferation.","evidence":"Co-IP, phosphorylation and kinase activity assays, NUMB isoform manipulation, and NUMB/WW45 double-KO mouse liver model","pmids":["37843276"],"confidence":"High","gaps":["Kinase responsible for SPTAN1 phosphorylation not identified","Density-sensing trigger mechanism unresolved"]},{"year":2024,"claim":"Established that αII-spectrin organizes the keratinocyte actomyosin cortex under E-cadherin guidance to dissipate tension and retain active EGFR/TRPV3 at the membrane for terminal differentiation.","evidence":"Conditional epidermal Sptan1 KO, laser ablation cortical tension measurement, and EGFR/TRPV3 membrane imaging (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Direct EGFR/TRPV3-spectrin binding not shown"]},{"year":2025,"claim":"Expanded SPTAN1 mechanism in three directions: axonal sodium channel anchoring, loss-of-function distal myopathy via NMD, and oncogenic lactylation-driven nuclear signaling in HCC.","evidence":"Zebrafish complementation for NaV localization; patient muscle qPCR/Western with NMD confirmation; mass spectrometry, co-IP, LLPS imaging and tumor models for lactylation","pmids":["39988451","40023774","41243220"],"confidence":"Medium","gaps":["Lactylation functional model from single lab","How myopathy phenotype arises from spectrin loss not mechanistically resolved","NaV anchoring partners not mapped"]},{"year":2026,"claim":"Linked reduced SPTAN1 to RAC1/c-FOS activation and altered calcium signaling in cystic kidney disease, with CRISPRa restoration rescuing cystic phenotypes.","evidence":"Kidney organoid-on-chip, transgenic mice, CRISPRa rescue, single-cell RNA-seq and live calcium imaging","pmids":["41742835"],"confidence":"Medium","gaps":["Mechanism connecting spectrin loss to RAC1 activation unresolved","Single lab"]},{"year":null,"claim":"The kinase that phosphorylates SPTAN1 during density sensing, and how its diverse scaffolding, repair, and lactylation functions are coordinated within one protein, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified SPTAN1 density-sensing kinase","No unified structural model linking heterodimerization, phase separation, and nuclear function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10,9,8]}],"complexes":["αII/βII spectrin heterodimer","αII-spectrin/FANCA/XPF DNA repair complex"],"partners":["SPTBN1","NUMB","MST1","WW45","FANCA","XPF","MLH1","CBFB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13813","full_name":"Spectrin alpha chain, non-erythrocytic 1","aliases":["Alpha-II spectrin","Fodrin alpha chain","Spectrin, non-erythroid alpha subunit"],"length_aa":2472,"mass_kda":284.5,"function":"Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cell cortex","url":"https://www.uniprot.org/uniprotkb/Q13813/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPTAN1","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SPTAN1","total_profiled":1310},"omim":[{"mim_id":"620540","title":"DEVELOPMENTAL DELAY WITH OR WITHOUT EPILEPSY; DEVEP","url":"https://www.omim.org/entry/620540"},{"mim_id":"620538","title":"SPASTIC PARAPLEGIA 91, AUTOSOMAL DOMINANT, WITH OR WITHOUT CEREBELLAR ATAXIA; SPG91","url":"https://www.omim.org/entry/620538"},{"mim_id":"620528","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 11; HMND11","url":"https://www.omim.org/entry/620528"},{"mim_id":"620253","title":"CATARACT 50 WITH OR WITHOUT GLAUCOMA; CTRCT50","url":"https://www.omim.org/entry/620253"},{"mim_id":"613477","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 5; DEE5","url":"https://www.omim.org/entry/613477"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPTAN1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13813","domains":[{"cath_id":"1.20.58.60","chopping":"13-147","consensus_level":"high","plddt":75.503,"start":13,"end":147},{"cath_id":"1.20.58.60","chopping":"175-367","consensus_level":"medium","plddt":85.6807,"start":175,"end":367},{"cath_id":"1.20.58.60","chopping":"677-740_753-760_774-809_817-852_859-873","consensus_level":"medium","plddt":78.5219,"start":677,"end":873},{"cath_id":"2.30.30.40","chopping":"966-1029","consensus_level":"medium","plddt":70.1141,"start":966,"end":1029},{"cath_id":"1.20.58.60","chopping":"1365-1458","consensus_level":"medium","plddt":86.155,"start":1365,"end":1458},{"cath_id":"1.20.58.60","chopping":"1583-1661","consensus_level":"medium","plddt":71.6754,"start":1583,"end":1661},{"cath_id":"1.20.58.60","chopping":"1684-1766","consensus_level":"medium","plddt":75.4804,"start":1684,"end":1766},{"cath_id":"1.20.58.60","chopping":"2002-2079","consensus_level":"medium","plddt":74.3006,"start":2002,"end":2079},{"cath_id":"1.10.238.10","chopping":"2216-2401","consensus_level":"medium","plddt":69.8522,"start":2216,"end":2401},{"cath_id":"1.10.287","chopping":"916-964_1061-1099","consensus_level":"medium","plddt":77.2007,"start":916,"end":1099}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13813","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13813-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13813-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPTAN1","jax_strain_url":"https://www.jax.org/strain/search?query=SPTAN1"},"sequence":{"accession":"Q13813","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13813.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13813/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13813"}},"corpus_meta":[{"pmid":"29050398","id":"PMC_29050398","title":"Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29050398","citation_count":74,"is_preprint":false},{"pmid":"25631096","id":"PMC_25631096","title":"SPTAN1 encephalopathy: distinct phenotypes and genotypes.","date":"2015","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25631096","citation_count":66,"is_preprint":false},{"pmid":"22722545","id":"PMC_22722545","title":"Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.","date":"2012","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22722545","citation_count":53,"is_preprint":false},{"pmid":"28938540","id":"PMC_28938540","title":"MicroRNA-128-3p regulates mitomycin C-induced DNA damage response in lung cancer cells through repressing SPTAN1.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28938540","citation_count":45,"is_preprint":false},{"pmid":"22429196","id":"PMC_22429196","title":"Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation.","date":"2012","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/22429196","citation_count":33,"is_preprint":false},{"pmid":"24456667","id":"PMC_24456667","title":"Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24456667","citation_count":26,"is_preprint":false},{"pmid":"30856214","id":"PMC_30856214","title":"Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer.","date":"2019","source":"PloS 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34590414","citation_count":7,"is_preprint":false},{"pmid":"34298848","id":"PMC_34298848","title":"SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34298848","citation_count":5,"is_preprint":false},{"pmid":"38891846","id":"PMC_38891846","title":"Erk Inhibition as a Promising Therapeutic Strategy for High IL-8-Secreting and Low SPTAN1-Expressing Colorectal Cancer.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38891846","citation_count":5,"is_preprint":false},{"pmid":"29025591","id":"PMC_29025591","title":"Identification of a novel CSF3R-SPTAN1 fusion gene in an atypical chronic myeloid leukemia patient with t(1;9)(p34;q34) by RNA-Seq.","date":"2017","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29025591","citation_count":5,"is_preprint":false},{"pmid":"40023774","id":"PMC_40023774","title":"Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.","date":"2025","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40023774","citation_count":4,"is_preprint":false},{"pmid":"41243220","id":"PMC_41243220","title":"Lactylated SPTAN1 Accelerates Hepatocellular Carcinoma Progression by Promoting NOTCH1/HES1 Activation and Immunosuppression.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41243220","citation_count":3,"is_preprint":false},{"pmid":"39371122","id":"PMC_39371122","title":"Heterozygous loss-of-function variants in SPTAN1 cause a novel early childhood onset distal myopathy with chronic neurogenic features.","date":"2024","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39371122","citation_count":3,"is_preprint":false},{"pmid":"34526651","id":"PMC_34526651","title":"SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia.","date":"2021","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34526651","citation_count":3,"is_preprint":false},{"pmid":"34934968","id":"PMC_34934968","title":"SPTAN1, APC, and FGFR3 Mutation Status and APOBEC Mutation Signatures are Predictive of Mitomycin C Response in Non-muscle-invasive Bladder Cancer.","date":"2021","source":"European urology open science","url":"https://pubmed.ncbi.nlm.nih.gov/34934968","citation_count":3,"is_preprint":false},{"pmid":"35219564","id":"PMC_35219564","title":"Neurochemistry evaluated by MR spectroscopy in a patient with SPTAN1-related developmental and epileptic encephalopathy.","date":"2022","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/35219564","citation_count":3,"is_preprint":false},{"pmid":"40261672","id":"PMC_40261672","title":"SPTAN1-Results of a Caregiver Survey.","date":"2025","source":"Journal of child and adolescent psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40261672","citation_count":2,"is_preprint":false},{"pmid":"35620303","id":"PMC_35620303","title":"Longitudinal neurodevelopmental profile of a pediatric patient with de novo SPTAN1, epilepsy, and left hippocampal sclerosis.","date":"2022","source":"Epilepsy & behavior reports","url":"https://pubmed.ncbi.nlm.nih.gov/35620303","citation_count":2,"is_preprint":false},{"pmid":"41742835","id":"PMC_41742835","title":"Deciphering the Impact of RAC1-SPTAN1 in ARPKD Cystogenesis Using Multifaceted Models.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41742835","citation_count":1,"is_preprint":false},{"pmid":"40999194","id":"PMC_40999194","title":"A heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/40999194","citation_count":1,"is_preprint":false},{"pmid":"40397273","id":"PMC_40397273","title":"Phenotypic and molecular characterization of a recurrent SPTAN1 mutation causing SPG91.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40397273","citation_count":0,"is_preprint":false},{"pmid":"39988451","id":"PMC_39988451","title":"Loss of Function SPTAN1 Variants Result in Ataxia and Intellectual Disability.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39988451","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.17.618796","title":"Spectrin coordinates cell shape and signaling essential for epidermal differentiation","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.17.618796","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.19.608697","title":"Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function","date":"2024-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.19.608697","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18830,"output_tokens":4256,"usd":0.060165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12390,"output_tokens":4005,"usd":0.081037,"stage2_stop_reason":"end_turn"},"total_usd":0.141202,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"SPTAN1 mutations within the α/β spectrin heterodimerization domain (specifically the amino acid stretch Asp2303 to Met2309 in the α20 repeat) cause αII/βII spectrin aggregate formation and accumulation of αII spectrin in the insoluble protein fraction, as demonstrated in patient-derived fibroblasts. Mutations outside this domain do not produce aggregates and are associated with milder phenotypes.\",\n      \"method\": \"Triton-X extraction (biochemical fractionation) and immunocytochemistry with fluorescence microscopy on patient fibroblasts; molecular modelling of mutant spectrin repeats\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and imaging in patient-derived cells, two orthogonal methods, single lab\",\n      \"pmids\": [\"29050398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In-frame mutations in the last two spectrin repeats (C-terminal region) of SPTAN1, which constitute the nucleation site for α/β spectrin heterodimer formation, exert dominant negative effects by altering heterodimer formation between αII and βII spectrin, leading to epileptic encephalopathy.\",\n      \"method\": \"Review and synthesis of patient genetic data combined with functional inference from aggregate formation studies in transfected cells (referenced from prior work)\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replicated across multiple patient reports and cell-based observations, but primarily synthesis/review; mechanism inferred from cellular aggregation data\",\n      \"pmids\": [\"25631096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"De novo in-frame SPTAN1 mutations (p.E2207del and p.R2308_M2309dup, and p.Q2202del) in the C-terminal domain induce different patterns of spectrin subunit aggregation in transfected neuronal cell lines, establishing that distinct mutations at this domain cause different aggregation phenotypes.\",\n      \"method\": \"Transfection of neuronal cell lines with mutant SPTAN1 constructs; immunocytochemistry to assess spectrin aggregation patterns\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-based functional assay in neuronal lines with defined mutations, single lab, two mutations compared\",\n      \"pmids\": [\"22258530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPTAN1 (αII spectrin) is a component of the αII Sp/FANCA/XPF DNA repair complex; miR-128-3p targets SPTAN1 to reduce its protein level via translational inhibition, thereby attenuating repair of DNA inter-strand crosslinks (ICLs), inducing cell cycle arrest and chromosomal instability in lung cancer cells treated with mitomycin C.\",\n      \"method\": \"Computational prediction and experimental validation (luciferase reporter/miRNA target assay); Western blot for protein level; co-immunoprecipitation for αII Sp/FANCA/XPF complex; cell cycle analysis; chromosomal aberration assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, knockdown, cell cycle assay), single lab\",\n      \"pmids\": [\"28938540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SPTAN1 physically interacts with MLH1 (mismatch repair protein) and regulates cellular migration; overexpression of SPTAN1 increases migration of MLH1-deficient cells, while siRNA knockdown of SPTAN1 decreases migration of MLH1-proficient cells, establishing a SPTAN1-dependent migration function.\",\n      \"method\": \"siRNA knockdown of SPTAN1 and MLH1; SPTAN1 overexpression; cellular motility assays in multiple cancer cell lines\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with defined phenotypic readout (migration), single lab, multiple cell lines\",\n      \"pmids\": [\"24456667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPTAN1 knockdown in colon cancer cell lines decreases cell viability, impairs cellular mobility, and reduces cell-cell contact formation, indicating roles in cell growth, motility, and adhesion.\",\n      \"method\": \"siRNA knockdown of SPTAN1 in CRC cell lines; cell viability assays; migration assays; microscopy for cell-cell contacts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple defined phenotypic readouts, single lab\",\n      \"pmids\": [\"30856214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPTAN1 acts as a cell density sensor upstream of Hippo signaling: at high cell density, SPTAN1 is phosphorylated, recruits NUMB1/2 to the plasma membrane, which sequesters MARK kinases at the membrane preventing their inhibition of MST1/2, enhancing WW45-MST1/2 interaction, activating Hippo signaling and suppressing YAP. At low density, SPTAN1 is dephosphorylated, NUMB moves to cytoplasm, MARKs inhibit MST1/2, and YAP is activated. NUMB isoforms 3/4 (truncated PTB domain) cannot interact with phospho-SPTAN1 and are upregulated in liver cancer.\",\n      \"method\": \"Co-immunoprecipitation (SPTAN1-NUMB interaction); phosphorylation studies; NUMB isoform knockdown/overexpression; MST1/2 kinase activity assays; double KO (NUMB/WW45) mouse liver model; YAP activity readout; liver organomegaly and tumorigenesis assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, KO mouse model, kinase assays, cell density experiments), mechanistic pathway placement established with in vivo validation\",\n      \"pmids\": [\"37843276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hair cell-specific knockout of Sptan1 in mice causes rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of hair cells from cochlear middle and apical turns. Sptan1 deficiency leads to decreased cell spreading, abnormal focal adhesion formation, and impaired integrin signaling in hair cells.\",\n      \"method\": \"Hair cell-specific Sptan1 conditional knockout mouse; auditory brainstem response testing; electron and fluorescence microscopy of stereocilia/cuticular plate morphology; focal adhesion and integrin signaling analysis in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal phenotypic readouts (auditory function, morphology, signaling), rigorous in vivo and in vitro methods\",\n      \"pmids\": [\"34708331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPTAN1 undergoes lactylation (at K1952 and K1957) in HBV-positive hepatocellular carcinoma tissue. AARS1 (alanyl-tRNA synthetase 1) mediates SPTAN1 lactylation, while HDAC1 acts as a delactylase. HBV infection induces HK2-driven lactate production, promoting SPTAN1 lactylation, which disrupts cytoplasmic SPTAN1 liquid-liquid phase separation and facilitates nuclear translocation. In the nucleus, lactylated SPTAN1 interacts with CBFB to activate NOTCH1/HES1 signaling, promoting HCC proliferation and immunosuppression via COX2/mPGES1/PGE2 pathway.\",\n      \"method\": \"Mass spectrometry for lactylation site identification; AARS1/HDAC1 overexpression and knockdown; Co-immunoprecipitation (SPTAN1-CBFB); live-cell imaging for LLPS and nuclear translocation; NOTCH1/HES1 reporter assays; preclinical tumor models with inhibitory peptides\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including MS, co-IP, and in vivo models, single lab, novel PTM with writer/eraser identified\",\n      \"pmids\": [\"41243220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Reduced SPTAN1 levels are a key regulator of RAC1 activation and cystic pathology in ARPKD models; SPTAN1-mutant kidney organoids and mice exhibit distal-nephron cysts with elevated RAC1/c-FOS expression and altered calcium signaling. Restoring SPTAN1 in PKHD1-/- organoids via CRISPR activation alleviates cystic phenotypes, normalizes intracellular calcium, and reduces RAC1/c-FOS expression.\",\n      \"method\": \"Kidney organoid-on-chip models; transgenic mice; CRISPR activation (CRISPRa) for SPTAN1 restoration; transcriptomics and single-cell RNA-seq; live calcium imaging; immunostaining for RAC1/c-FOS\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal models (organoids, mice, patient samples), gain-of-function rescue with defined molecular readouts, single lab\",\n      \"pmids\": [\"41742835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss-of-function variants in SPTAN1 (frameshift, nonsense, splice-site) in muscle cause distal myopathy with nonsense-mediated decay of SPTAN1 mRNA confirmed in patient-derived muscle tissue. Protein expression was reduced concordantly in affected patients.\",\n      \"method\": \"qPCR and Western blotting on patient-derived muscle tissue; mRNA expression analysis and cDNA sequencing; muscle biopsy histopathology; electrophysiology; muscle MRI/CT\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular analysis of patient tissue with NMD confirmation, multiple families, multi-center collaboration\",\n      \"pmids\": [\"40023774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, the SPTAN1 variant p.(Gln1448Pro) reduces protein abundance and impairs SPTAN1 localization to axons, and fails to restore voltage-gated sodium channel localization in sptan1-null axons, establishing a role for SPTAN1 in anchoring voltage-gated sodium channels at axons.\",\n      \"method\": \"Ectopic expression of wild-type and variant sptan1 in zebrafish; immunofluorescence for SPTAN1 and voltage-gated sodium channel localization in axons; behavioral motility assays; protein abundance quantification\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue/complementation experiment in zebrafish with defined molecular readout (NaV channel localization), single lab\",\n      \"pmids\": [\"39988451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of αII-spectrin (Sptan1) in mouse epidermis alters cell shape in all layers and impairs epidermal differentiation and barrier formation. αII-spectrin organizes the keratinocyte actomyosin cortex, and E-cadherin guides differential gradients of actin and spectrin to regulate layer-specific sub-membraneous spectrin-actomyosin network organization. This organization is required to dissipate tension, maintain structural integrity, and retain active EGFR and TRPV3 at the membrane in upper layers to induce terminal differentiation.\",\n      \"method\": \"Conditional Sptan1 knockout in mouse epidermis; high-resolution imaging; laser ablation (cortical tension); immunofluorescence for EGFR and TRPV3 membrane retention; barrier function assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, laser ablation, imaging), in vivo model, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Irregular αII-spectrin aggregation was observed in fibroblasts from patients carrying SPTAN1 variants p.(Arg19Trp) and p.(Glu2207del), extending the aggregation phenotype beyond the C-terminal heterodimerization domain to include N-terminal variants.\",\n      \"method\": \"Immunocytochemistry and fluorescence microscopy on patient-derived fibroblasts\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (immunocytochemistry), single lab, limited functional follow-up\",\n      \"pmids\": [\"36331550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Low SPTAN1 expression is associated with enhanced ERK phosphorylation (via RAS-mediated RAF/MEK/ERK pathway activation) and increased IL-8 secretion in CRC cell lines with stable SPTAN1 knockdown, and ERK inhibition reduces IL-8 secretion in these cells.\",\n      \"method\": \"Stable SPTAN1 knockdown cell lines (SW480, SW620, HT-29); Western blot for ERK phosphorylation; IL-8 ELISA; pharmacological ERK inhibition (U0126)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with defined signaling readout, but indirect pathway placement, single lab, limited mechanistic depth\",\n      \"pmids\": [\"38891846\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPTAN1 (αII-spectrin/α-fodrin) is a plasma membrane-stabilizing cytoskeletal scaffolding protein that forms obligate αII/βII spectrin heterodimers via its C-terminal nucleation domain; in-frame mutations in this domain disrupt heterodimer formation and cause pathological protein aggregation. It functions as a cell density sensor by undergoing phosphorylation at high density to recruit NUMB1/2 to the plasma membrane, sequestering MARK kinases and thereby activating Hippo/MST1/2 signaling to suppress YAP-driven proliferation. SPTAN1 anchors voltage-gated sodium channels at axons, participates in a FANCA/XPF DNA repair complex at inter-strand crosslinks, organizes the sub-membraneous actomyosin cortex to regulate cell shape and EGFR/TRPV3 membrane retention in keratinocyte differentiation, supports focal adhesion/integrin signaling in cochlear hair cells, regulates cellular migration downstream of MLH1, and can undergo oncogenic lactylation (at K1952/K1957, mediated by AARS1 and reversed by HDAC1) that drives nuclear translocation and CBFB-mediated NOTCH1/HES1 activation in hepatocellular carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPTAN1 (αII-spectrin/α-fodrin) is a sub-membraneous cytoskeletal scaffolding protein that forms obligate αII/βII spectrin heterodimers through a C-terminal nucleation domain in its last spectrin repeats, organizing the cortical actomyosin network that maintains cell shape, tissue integrity, and membrane protein anchoring [#1, #12]. In-frame mutations within this heterodimerization domain act dominant-negatively, disrupting heterodimer assembly and driving αII/βII spectrin into insoluble aggregates, the molecular lesion underlying SPTAN1-related epileptic encephalopathy [#0, #1, #2]. Through this cortical scaffolding role, SPTAN1 anchors voltage-gated sodium channels at axons [#11], supports focal adhesion and integrin signaling required for cochlear hair cell stereocilia and cuticular plate formation [#7], and retains active EGFR and TRPV3 at the keratinocyte membrane to drive epidermal terminal differentiation and barrier formation [#12]. Beyond structural scaffolding, SPTAN1 functions as a cell density sensor upstream of Hippo signaling: at high density it is phosphorylated and recruits NUMB1/2 to the plasma membrane, sequestering MARK kinases to relieve their inhibition of MST1/2 and thereby suppressing YAP-driven proliferation [#6]. SPTAN1 additionally participates in DNA inter-strand crosslink repair as a component of an αII-spectrin/FANCA/XPF complex [#3], physically interacts with MLH1 to regulate cell migration [#4], and supports cancer cell viability, motility, and cell-cell contact [#5]. Loss-of-function variants causing nonsense-mediated decay produce a distal myopathy [#10], and reduced SPTAN1 drives RAC1/c-FOS activation and cystic pathology in ARPKD kidney models [#9]. In hepatocellular carcinoma, AARS1-mediated lactylation at K1952/K1957 (reversed by HDAC1) disrupts cytoplasmic SPTAN1 phase separation, promoting nuclear translocation and CBFB-dependent NOTCH1/HES1 activation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that distinct de novo in-frame mutations in the SPTAN1 C-terminal domain produce different spectrin aggregation phenotypes, linking specific lesions to molecular pathology.\",\n      \"evidence\": \"Transfection of mutant SPTAN1 into neuronal cell lines with immunocytochemistry of aggregation patterns\",\n      \"pmids\": [\"22258530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how aggregation translates to neuronal dysfunction\", \"No quantification of heterodimer disruption per mutation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a physical SPTAN1-MLH1 interaction and a SPTAN1-dependent migration function, extending SPTAN1 beyond a purely structural role into mismatch-repair-linked motility control.\",\n      \"evidence\": \"siRNA knockdown, overexpression, and motility assays across multiple cancer cell lines\",\n      \"pmids\": [\"24456667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not mapped to specific domains\", \"Mechanism linking MLH1 status to migration unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Synthesized patient and cell data to define the C-terminal nucleation site as the heterodimerization hotspot whose mutation exerts dominant-negative effects in epileptic encephalopathy.\",\n      \"evidence\": \"Review and synthesis of patient genetics with cell-based aggregation inference\",\n      \"pmids\": [\"25631096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primarily synthesis rather than new experiment\", \"Genotype-phenotype mapping incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SPTAN1 within an αII-spectrin/FANCA/XPF DNA repair complex and showed miR-128-3p suppression of SPTAN1 attenuates inter-strand crosslink repair, defining a genome-maintenance role.\",\n      \"evidence\": \"Co-IP, luciferase miRNA target assay, Western blot, cell cycle and chromosomal aberration assays in lung cancer cells\",\n      \"pmids\": [\"28938540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural role of SPTAN1 in repair not defined\", \"Single lung cancer context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized the pathogenic aggregation defect to the Asp2303-Met2309 stretch of the α20 repeat, demonstrating that only heterodimerization-domain mutations drive insoluble αII spectrin accumulation.\",\n      \"evidence\": \"Triton-X biochemical fractionation, immunocytochemistry on patient fibroblasts, and molecular modelling\",\n      \"pmids\": [\"29050398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how insoluble aggregates impair neuronal function\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that SPTAN1 supports colon cancer cell viability, motility, and cell-cell contact formation, generalizing its role in cell adhesion and growth.\",\n      \"evidence\": \"siRNA knockdown with viability, migration, and microscopy readouts in CRC lines\",\n      \"pmids\": [\"30856214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors downstream not identified\", \"Phenotypes correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed via hair cell conditional knockout that SPTAN1 is required for stereocilia/cuticular plate formation and hearing through focal adhesion and integrin signaling, defining a tissue-specific cytoskeletal role.\",\n      \"evidence\": \"Hair cell-specific Sptan1 conditional KO mouse, ABR testing, EM/fluorescence morphology, integrin signaling analysis in HEI-OC1 cells\",\n      \"pmids\": [\"34708331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct integrin-spectrin biochemical linkage not resolved\", \"Relevance to human deafness inferred\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined SPTAN1 as a phosphorylation-dependent cell density sensor that recruits NUMB1/2 to sequester MARK kinases and activate Hippo/MST1/2 signaling, suppressing YAP proliferation.\",\n      \"evidence\": \"Co-IP, phosphorylation and kinase activity assays, NUMB isoform manipulation, and NUMB/WW45 double-KO mouse liver model\",\n      \"pmids\": [\"37843276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for SPTAN1 phosphorylation not identified\", \"Density-sensing trigger mechanism unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that αII-spectrin organizes the keratinocyte actomyosin cortex under E-cadherin guidance to dissipate tension and retain active EGFR/TRPV3 at the membrane for terminal differentiation.\",\n      \"evidence\": \"Conditional epidermal Sptan1 KO, laser ablation cortical tension measurement, and EGFR/TRPV3 membrane imaging (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Direct EGFR/TRPV3-spectrin binding not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded SPTAN1 mechanism in three directions: axonal sodium channel anchoring, loss-of-function distal myopathy via NMD, and oncogenic lactylation-driven nuclear signaling in HCC.\",\n      \"evidence\": \"Zebrafish complementation for NaV localization; patient muscle qPCR/Western with NMD confirmation; mass spectrometry, co-IP, LLPS imaging and tumor models for lactylation\",\n      \"pmids\": [\"39988451\", \"40023774\", \"41243220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation functional model from single lab\", \"How myopathy phenotype arises from spectrin loss not mechanistically resolved\", \"NaV anchoring partners not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked reduced SPTAN1 to RAC1/c-FOS activation and altered calcium signaling in cystic kidney disease, with CRISPRa restoration rescuing cystic phenotypes.\",\n      \"evidence\": \"Kidney organoid-on-chip, transgenic mice, CRISPRa rescue, single-cell RNA-seq and live calcium imaging\",\n      \"pmids\": [\"41742835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting spectrin loss to RAC1 activation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The kinase that phosphorylates SPTAN1 during density sensing, and how its diverse scaffolding, repair, and lactylation functions are coordinated within one protein, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified SPTAN1 density-sensing kinase\", \"No unified structural model linking heterodimerization, phase separation, and nuclear function\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10, 9, 8]}\n    ],\n    \"complexes\": [\n      \"αII/βII spectrin heterodimer\",\n      \"αII-spectrin/FANCA/XPF DNA repair complex\"\n    ],\n    \"partners\": [\n      \"SPTBN1\",\n      \"NUMB\",\n      \"MST1\",\n      \"WW45\",\n      \"FANCA\",\n      \"XPF\",\n      \"MLH1\",\n      \"CBFB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}