{"gene":"SEZ6","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1995,"finding":"SEZ6 encodes a type I transmembrane protein with a signal sequence, threonine-rich domain, five complement control protein (CCP/SCR) domains (complement C3b/C4b binding sites), two CUB domain-like repeats, one transmembrane domain, and a short cytoplasmic tail, suggesting roles in complement-related signaling and cell-cell recognition.","method":"cDNA cloning, sequence analysis, domain prediction","journal":"Brain research. Molecular brain research","confidence":"High","confidence_rationale":"Tier 1 — original cloning with full sequence/domain characterization, replicated in two papers from same year","pmids":["7723619","7488116"],"is_preprint":false},{"year":1995,"finding":"SEZ6 protein is post-translationally modified (glycosylated) and expressed in cerebrum and cerebellum; PCR identified two additional isoforms: one encoding a membrane protein with a different C-terminal region and one encoding a secreted protein with two SCRs and one CUB-like domain.","method":"In vitro translation, immunoblot with anti-SEZ6 peptide antibody, PCR isoform analysis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro translation and immunoblot, multiple isoforms experimentally confirmed","pmids":["7488116"],"is_preprint":false},{"year":2007,"finding":"Sez6 is required for normal dendritic arborization of cortical pyramidal neurons; loss of Sez6 in null mice causes excess short dendrites and excessive neurite branching in cultured neurons. Membrane-bound Sez6 exerts an anti-branching effect while secreted Sez6 has opposing (pro-branching) activity. Layer V pyramidal neurons in knockout mice show reduced excitatory postsynaptic responses and reduced dendritic spine density with diminished PSD-95 puncta.","method":"Sez6 null mutant mouse analysis, overexpression of individual isoforms in knockout neurons, electrophysiology, immunostaining for PSD-95, cultured neuron assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotypes, isoform rescue experiments, multiple orthogonal methods, highly cited foundational paper","pmids":["18031681"],"is_preprint":false},{"year":2007,"finding":"Membrane-bound and secreted Sez6 isoforms have opposing effects on dendritic branching, with cell-surface protein complexes involving Sez6 sculpting the dendritic arbor and enhancing synaptic connectivity.","method":"Overexpression of individual Sez6 isoforms in sez-6 knockout cortical neurons under basal and depolarizing conditions","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific rescue in KO neurons with depolarization condition controls","pmids":["18031681"],"is_preprint":false},{"year":2011,"finding":"Sez6 protein localizes to dendrites of hippocampal and cortical pyramidal neurons neonatally, then relocates perisomatic after postnatal day 10, suggesting a developmental shift in function during forebrain maturation.","method":"Immunohistochemistry with new anti-Sez6 antibody validated by Western blot, temporal and spatial expression analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with validated antibody, but functional consequence of relocalization not directly tested","pmids":["21334315"],"is_preprint":false},{"year":2011,"finding":"Sez-6 promotes neurite outgrowth in PC12 cells via a mechanism involving PKCγ signaling; knockdown of Sez-6 by shRNA inhibits neurite outgrowth and increases PKCγ protein levels in differentiated cells.","method":"shRNA knockdown in PC12 cells, NGF differentiation, Western blot for PKCγ","journal":"Zeitschrift fur Naturforschung. C, Journal of biosciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method, pathway placement based on correlation of PKCγ levels without direct epistasis","pmids":["22351987"],"is_preprint":false},{"year":2015,"finding":"N-glycosylation of Sez6 regulates its cell-surface distribution and function; the SC4-7 glycosylation cluster is specifically required for filopodia-like protrusion formation, while removal of SC1-3 or SC4-7 clusters reduces neurite formation. Unglycosylated Sez6 is still transported to the membrane but shows altered distribution.","method":"N-glycosylation cluster deletion mutants transfected into Neuro2a cells, cell surface distribution analysis, conditioned medium analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of specific glycosylation sites with functional readouts in neuronal cell line","pmids":["25960298"],"is_preprint":false},{"year":2018,"finding":"Sez6 is a substrate of BACE1 (β-secretase); BACE1 cleaves the type I transmembrane isoform of Sez6, shedding its extracellular domain from the neuron surface. Enhanced BACE1-cleavage of Sez6 and Sez6L is detected in NPC1-null mouse brains. Sez6 and Sez6L show increased punctate staining within the endolysosomal pathway in NPC1-null neurons, indicating a trafficking defect underlies enhanced BACE1 proteolysis.","method":"Immunoblot of BACE1 cleavage products in NPC1-null vs. wild-type mouse brains, immunofluorescence of endolysosomal colocalization in primary cortical neurons","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical detection of cleavage products in vivo and cell-based localization, but mechanism of BACE1 substrate relationship established in prior work","pmids":["29979789"],"is_preprint":false},{"year":2019,"finding":"The BACE1-shed extracellular domain of Sez6 is detectable in human cerebrospinal fluid, and Sez6 levels are elevated in CSF of patients with inflammatory pain conditions. Sez6 knockout mice show attenuated pain behaviors after peripheral nerve injury.","method":"Western blot of CSF from surgical patients; behavioral analysis of sez6 knockout mice after nerve injury","journal":"Pain reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse behavioral phenotype combined with human CSF detection; two orthogonal approaches in one study","pmids":["31041421"],"is_preprint":false},{"year":2020,"finding":"Sez6 family proteins (Sez6, Sez6L, Sez6L2) collectively regulate dendritic spine structure and density; triple knockout (TKO) mice lacking all three family members show reduced hippocampal spine density and shift toward immature spine morphologies in somatosensory cortex, along with impaired motor learning and cognitive flexibility.","method":"Sez6 triple knockout mice, spine morphology analysis, behavioral testing (motor coordination, Morris water maze, working memory)","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 — clean TKO with defined structural and behavioral phenotypes, multiple orthogonal readouts","pmids":["31711114"],"is_preprint":false},{"year":2021,"finding":"Sez6, Sez6L, and Sez6L2 function as complement inhibitors: they inhibit C3b/iC3b opsonization by the classical and alternative complement pathways. Using Sez6L2 as representative, the family accelerates dissociation of C3 convertases and acts as a cofactor for Factor I to facilitate cleavage of C3b (but not C4b).","method":"Complement inhibition assays (classical and alternative pathway opsonization), C3 convertase decay assay, Factor I cofactor assay","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple in vitro biochemical assays with reconstitution of complement pathway steps and defined mechanistic dissection","pmids":["33936031"],"is_preprint":false},{"year":2022,"finding":"In 5xFAD Alzheimer's disease mouse brains, BACE1 accumulation in peri-plaque regions does not enhance proteolytic cleavage of Sez6 or Sez6L, but both proteins show altered distribution in areas surrounding Aβ plaques, distinct from APP/BACE1/LAMP1 localization.","method":"Western blot for Sez6/Sez6L cleavage products in 5xFAD brains, immunofluorescence localization relative to Aβ plaques","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical and immunofluorescence in validated AD mouse model, but single lab","pmids":["35998821"],"is_preprint":false},{"year":2022,"finding":"Sez6 alternative splicing produces three isoforms (dominant transmembrane, and two recessive isoforms including a secreted form) with brain-area-specific splicing patterns; the striatum shows a characteristic recessive isoform pattern. Neuronal activation by convulsant drug increases recessive isoforms similarly to the dominant isoform in cultured cortical neurons.","method":"qPCR of isoform-specific primers across brain regions and cultured cortical neurons under convulsant stimulation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — expression-level isoform analysis without functional readout of specific isoform activities","pmids":["36368155"],"is_preprint":false},{"year":2022,"finding":"SEZ6 is rapidly internalized upon antibody binding to its extracellular domain on the cell surface, enabling antibody-drug conjugate payload delivery in SCLC cells.","method":"Antibody internalization assay in SEZ6-expressing SCLC cell lines, in vitro and in vivo ADC efficacy","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — direct internalization assay combined with in vitro and in vivo efficacy readout","pmids":["35642431"],"is_preprint":false}],"current_model":"SEZ6 is a type I transmembrane glycoprotein with CCP/SCR and CUB domains that functions as a complement inhibitor (accelerating C3 convertase decay and acting as a Factor I cofactor for C3b cleavage), a BACE1 substrate whose shedding releases a soluble ectodomain, and a regulator of neuronal dendritic arborization and spine density where membrane-bound and secreted isoforms exert opposing effects on branching, collectively shaping excitatory synaptic connectivity in the developing brain."},"narrative":{"teleology":[{"year":1995,"claim":"Cloning of SEZ6 revealed a novel transmembrane architecture with complement-related CCP/SCR and CUB domains, establishing that a seizure-responsive gene encodes a protein with potential complement-signaling and cell-recognition functions.","evidence":"cDNA cloning, sequence analysis, and domain prediction from seizure-induced brain libraries; in vitro translation and immunoblot confirmed glycosylation and multiple isoforms including a secreted form","pmids":["7723619","7488116"],"confidence":"High","gaps":["No functional assay for complement binding or cell recognition","Ligand or binding partner unknown","Isoform-specific functions not tested"]},{"year":2007,"claim":"Knockout mouse studies answered the question of SEZ6's neuronal function, demonstrating that it is required for normal dendritic arborization, spine density, and excitatory synaptic connectivity, with membrane-bound and secreted isoforms exerting opposing effects on branching.","evidence":"Sez6 null mutant mice, isoform-specific rescue in cultured KO neurons, electrophysiology, PSD-95 immunostaining","pmids":["18031681"],"confidence":"High","gaps":["Molecular mechanism by which membrane-bound Sez6 inhibits branching is unknown","Direct binding partners mediating dendritic effects not identified","Signaling pathways downstream of Sez6 at the membrane not defined"]},{"year":2011,"claim":"Developmental relocalization of Sez6 protein from dendrites to the perisomatic region after postnatal day 10 indicated a temporal shift in function, while a separate study linked Sez6 to PKCγ-dependent neurite outgrowth.","evidence":"Immunohistochemistry with validated antibody across postnatal time points; shRNA knockdown in PC12 cells with PKCγ Western blot","pmids":["21334315","22351987"],"confidence":"Medium","gaps":["Functional consequence of relocalization not directly tested","PKCγ link based on correlation without direct epistasis experiments","Whether PKCγ pathway operates in primary neurons is untested"]},{"year":2015,"claim":"Site-directed mutagenesis of N-glycosylation clusters showed that specific glycan modifications regulate Sez6 cell-surface distribution and filopodia formation, providing the first post-translational mechanism controlling its activity.","evidence":"Glycosylation cluster deletion mutants in Neuro2a cells with surface distribution and morphology analysis","pmids":["25960298"],"confidence":"Medium","gaps":["Not validated in primary neurons","How glycosylation affects ligand binding or complement function unknown","Whether glycosylation modulates BACE1 cleavage site accessibility not tested"]},{"year":2018,"claim":"Identification of SEZ6 as a BACE1 substrate answered how its ectodomain is shed, and revealed that endolysosomal trafficking defects (as in NPC1 deficiency) enhance BACE1-mediated cleavage.","evidence":"Immunoblot of BACE1 cleavage products in NPC1-null versus wild-type mouse brains; endolysosomal colocalization in primary cortical neurons","pmids":["29979789"],"confidence":"Medium","gaps":["BACE1 cleavage site on Sez6 not mapped","Functional consequence of enhanced shedding in NPC1 disease context not determined","Whether soluble ectodomain retains complement-inhibitory activity unknown"]},{"year":2019,"claim":"Detection of shed Sez6 ectodomain in human CSF and attenuated pain behavior in Sez6 knockout mice extended SEZ6 function beyond dendritic development to peripheral nociceptive signaling.","evidence":"Western blot of CSF from surgical patients; behavioral analysis of Sez6 knockout mice after peripheral nerve injury","pmids":["31041421"],"confidence":"Medium","gaps":["Mechanism linking Sez6 to pain signaling not identified","Whether CSF Sez6 is functionally active or a degradation product unknown","Cell types contributing to CSF Sez6 not determined"]},{"year":2020,"claim":"Triple knockout of all Sez6 family members established that the family collectively and non-redundantly regulates spine density, spine maturation, motor learning, and cognitive flexibility.","evidence":"Sez6/Sez6L/Sez6L2 triple knockout mice with spine morphology analysis and behavioral testing","pmids":["31711114"],"confidence":"High","gaps":["Individual contributions of each family member to spine phenotype not fully dissected","Downstream signaling pathways shared or distinct among family members unknown","Whether complement inhibition contributes to spine phenotypes not tested"]},{"year":2021,"claim":"Biochemical reconstitution demonstrated that SEZ6 family proteins are bona fide complement inhibitors that accelerate C3 convertase decay and serve as Factor I cofactors for C3b cleavage, finally assigning a molecular activity to the CCP domains.","evidence":"Classical and alternative pathway opsonization assays, C3 convertase decay acceleration assay, Factor I cofactor assay with purified components","pmids":["33936031"],"confidence":"High","gaps":["Whether complement inhibition occurs in vivo on neuronal surfaces not shown","Relative potency of Sez6 versus Sez6L2 in complement assays not directly compared","Structural basis for C3b selectivity over C4b unknown"]},{"year":2022,"claim":"Studies in AD mouse models, isoform splicing analysis, and antibody-drug conjugate work collectively refined the understanding of Sez6 processing and trafficking: Sez6 shows altered peri-plaque distribution without enhanced cleavage in 5xFAD mice, brain-region-specific alternative splicing, and efficient internalization from the cell surface upon antibody binding.","evidence":"Western blot and immunofluorescence in 5xFAD brains; qPCR of isoform-specific primers across brain regions; antibody internalization assays in SCLC cell lines with in vivo ADC efficacy","pmids":["35998821","36368155","35642431"],"confidence":"Medium","gaps":["Mechanism of Sez6 redistribution around amyloid plaques not defined","Functional significance of brain-region-specific splicing patterns untested","Internalization pathway and endosomal routing upon antibody binding not characterized"]},{"year":null,"claim":"Key open questions remain: what are the direct binding partners through which membrane-bound Sez6 regulates dendritic branching and spine density, whether complement inhibition by Sez6 at the neuronal surface contributes to synapse protection in vivo, and what the structural basis is for isoform-specific opposing functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct neuronal binding partner identified for dendritic phenotype","In vivo complement inhibition at synapses not demonstrated","No structural model of Sez6 ectodomain exists","Relationship between BACE1 shedding and complement-inhibitory function not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4,6,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,9]}],"complexes":[],"partners":["BACE1","CFI","C3B","SEZ6L","SEZ6L2"],"other_free_text":[]},"mechanistic_narrative":"SEZ6 is a type I transmembrane glycoprotein that regulates dendritic arborization, spine density, and excitatory synaptic connectivity in the developing brain while also functioning as a complement pathway inhibitor. Its ectodomain contains five CCP/SCR domains and two CUB-like repeats; alternative splicing generates membrane-bound and secreted isoforms that exert opposing effects on dendritic branching—membrane-bound Sez6 suppresses branching whereas secreted Sez6 promotes it—and loss of Sez6 in knockout mice results in excess short dendrites, reduced spine density, diminished PSD-95 puncta, and attenuated excitatory postsynaptic responses [PMID:18031681, PMID:31711114]. SEZ6 family members inhibit C3b opsonization by accelerating C3 convertase decay and serving as cofactors for Factor I–mediated cleavage of C3b, establishing a direct role in complement regulation at the neuronal surface [PMID:33936031]. The transmembrane isoform is a BACE1 substrate whose ectodomain shedding releases a soluble fragment detectable in cerebrospinal fluid, and N-glycosylation of specific CCP clusters governs cell-surface distribution and neurite-promoting activity [PMID:29979789, PMID:25960298]."},"prefetch_data":{"uniprot":{"accession":"Q53EL9","full_name":"Seizure protein 6 homolog","aliases":[],"length_aa":994,"mass_kda":107.4,"function":"May play a role in cell-cell recognition and in neuronal membrane signaling. Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. Involved in the development of appropriate excitatory synaptic connectivity (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q53EL9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEZ6","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEZ6","total_profiled":1310},"omim":[{"mim_id":"616667","title":"SEZ6-LIKE PROTEIN 2; SEZ6L2","url":"https://www.omim.org/entry/616667"},{"mim_id":"616666","title":"SEIZURE-RELATED 6, MOUSE, HOMOLOG OF; SEZ6","url":"https://www.omim.org/entry/616666"},{"mim_id":"607021","title":"SEZ6-LIKE PROTEIN; SEZ6L","url":"https://www.omim.org/entry/607021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":109.8}],"url":"https://www.proteinatlas.org/search/SEZ6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q53EL9","domains":[{"cath_id":"2.60.120.290","chopping":"246-258_268-355","consensus_level":"high","plddt":84.6592,"start":246,"end":355},{"cath_id":"2.60.120.290","chopping":"412-590","consensus_level":"medium","plddt":90.0067,"start":412,"end":590},{"cath_id":"2.60.120.290","chopping":"592-706","consensus_level":"medium","plddt":88.0519,"start":592,"end":706},{"cath_id":"2.10.70.10","chopping":"720-768","consensus_level":"medium","plddt":85.9539,"start":720,"end":768},{"cath_id":"2.10.70.10","chopping":"781-833","consensus_level":"high","plddt":86.1313,"start":781,"end":833},{"cath_id":"2.10.70.10","chopping":"839-898","consensus_level":"high","plddt":81.0738,"start":839,"end":898}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EL9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EL9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EL9-F1-predicted_aligned_error_v6.png","plddt_mean":69.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEZ6","jax_strain_url":"https://www.jax.org/strain/search?query=SEZ6"},"sequence":{"accession":"Q53EL9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EL9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EL9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EL9"}},"corpus_meta":[{"pmid":"18031681","id":"PMC_18031681","title":"Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/18031681","citation_count":121,"is_preprint":false},{"pmid":"35642431","id":"PMC_35642431","title":"ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.","date":"2022","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35642431","citation_count":50,"is_preprint":false},{"pmid":"31711114","id":"PMC_31711114","title":"Lack of Sez6 Family Proteins Impairs Motor Functions, Short-Term Memory, and Cognitive Flexibility and Alters Dendritic Spine Properties.","date":"2020","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/31711114","citation_count":45,"is_preprint":false},{"pmid":"7723619","id":"PMC_7723619","title":"Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA.","date":"1995","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7723619","citation_count":41,"is_preprint":false},{"pmid":"33936031","id":"PMC_33936031","title":"The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33936031","citation_count":32,"is_preprint":false},{"pmid":"7488116","id":"PMC_7488116","title":"Cloning and characterization of seizure-related gene, SEZ-6.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7488116","citation_count":32,"is_preprint":false},{"pmid":"12351182","id":"PMC_12351182","title":"Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12351182","citation_count":25,"is_preprint":false},{"pmid":"21334315","id":"PMC_21334315","title":"The distribution of the seizure-related gene 6 (Sez-6) protein during postnatal development of the mouse forebrain suggests multiple functions for this protein: an analysis using a new antibody.","date":"2011","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/21334315","citation_count":22,"is_preprint":false},{"pmid":"21785725","id":"PMC_21785725","title":"The Role of Seizure-Related SEZ6 as a Susceptibility Gene in Febrile Seizures.","date":"2011","source":"Neurology research international","url":"https://pubmed.ncbi.nlm.nih.gov/21785725","citation_count":20,"is_preprint":false},{"pmid":"9073173","id":"PMC_9073173","title":"SEZ-6: promoter selectivity, genomic structure and localized expression in the brain.","date":"1997","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9073173","citation_count":19,"is_preprint":false},{"pmid":"29979789","id":"PMC_29979789","title":"BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29979789","citation_count":14,"is_preprint":false},{"pmid":"34135477","id":"PMC_34135477","title":"ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment.","date":"2021","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/34135477","citation_count":12,"is_preprint":false},{"pmid":"30309378","id":"PMC_30309378","title":"Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H.","date":"2018","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30309378","citation_count":12,"is_preprint":false},{"pmid":"19662096","id":"PMC_19662096","title":"Seizure-related gene 6 (Sez-6) in amacrine cells of the rodent retina and the consequence of gene deletion.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19662096","citation_count":10,"is_preprint":false},{"pmid":"31041421","id":"PMC_31041421","title":"Sez6 levels are elevated in cerebrospinal fluid of patients with inflammatory pain-associated conditions.","date":"2019","source":"Pain reports","url":"https://pubmed.ncbi.nlm.nih.gov/31041421","citation_count":8,"is_preprint":false},{"pmid":"38050039","id":"PMC_38050039","title":"Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6-Targeting Antibody-Drug Conjugate.","date":"2024","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/38050039","citation_count":5,"is_preprint":false},{"pmid":"39324657","id":"PMC_39324657","title":"Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma.","date":"2025","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39324657","citation_count":4,"is_preprint":false},{"pmid":"25960298","id":"PMC_25960298","title":"N-Glycosylation modulates filopodia-like protrusions induced by sez-6 through regulating the distribution of this protein on the cell surface.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25960298","citation_count":3,"is_preprint":false},{"pmid":"40699376","id":"PMC_40699376","title":"Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia.","date":"2025","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40699376","citation_count":2,"is_preprint":false},{"pmid":"40911432","id":"PMC_40911432","title":"Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.","date":"2025","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/40911432","citation_count":2,"is_preprint":false},{"pmid":"35998821","id":"PMC_35998821","title":"Amyloid-ß plaque formation and BACE1 accumulation in the brains of a 5xFAD Alzheimer's disease mouse model is associated with altered distribution and not proteolysis of BACE1 substrates Sez6 and Sez6L.","date":"2022","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/35998821","citation_count":1,"is_preprint":false},{"pmid":"22351987","id":"PMC_22351987","title":"Sez-6 may play an important role in neurite outgrowth through the PKCgamma signaling pathways.","date":"2011","source":"Zeitschrift fur Naturforschung. 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Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with full sequence/domain characterization, replicated in two papers from same year\",\n      \"pmids\": [\"7723619\", \"7488116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SEZ6 protein is post-translationally modified (glycosylated) and expressed in cerebrum and cerebellum; PCR identified two additional isoforms: one encoding a membrane protein with a different C-terminal region and one encoding a secreted protein with two SCRs and one CUB-like domain.\",\n      \"method\": \"In vitro translation, immunoblot with anti-SEZ6 peptide antibody, PCR isoform analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro translation and immunoblot, multiple isoforms experimentally confirmed\",\n      \"pmids\": [\"7488116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sez6 is required for normal dendritic arborization of cortical pyramidal neurons; loss of Sez6 in null mice causes excess short dendrites and excessive neurite branching in cultured neurons. Membrane-bound Sez6 exerts an anti-branching effect while secreted Sez6 has opposing (pro-branching) activity. Layer V pyramidal neurons in knockout mice show reduced excitatory postsynaptic responses and reduced dendritic spine density with diminished PSD-95 puncta.\",\n      \"method\": \"Sez6 null mutant mouse analysis, overexpression of individual isoforms in knockout neurons, electrophysiology, immunostaining for PSD-95, cultured neuron assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotypes, isoform rescue experiments, multiple orthogonal methods, highly cited foundational paper\",\n      \"pmids\": [\"18031681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Membrane-bound and secreted Sez6 isoforms have opposing effects on dendritic branching, with cell-surface protein complexes involving Sez6 sculpting the dendritic arbor and enhancing synaptic connectivity.\",\n      \"method\": \"Overexpression of individual Sez6 isoforms in sez-6 knockout cortical neurons under basal and depolarizing conditions\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific rescue in KO neurons with depolarization condition controls\",\n      \"pmids\": [\"18031681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sez6 protein localizes to dendrites of hippocampal and cortical pyramidal neurons neonatally, then relocates perisomatic after postnatal day 10, suggesting a developmental shift in function during forebrain maturation.\",\n      \"method\": \"Immunohistochemistry with new anti-Sez6 antibody validated by Western blot, temporal and spatial expression analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with validated antibody, but functional consequence of relocalization not directly tested\",\n      \"pmids\": [\"21334315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sez-6 promotes neurite outgrowth in PC12 cells via a mechanism involving PKCγ signaling; knockdown of Sez-6 by shRNA inhibits neurite outgrowth and increases PKCγ protein levels in differentiated cells.\",\n      \"method\": \"shRNA knockdown in PC12 cells, NGF differentiation, Western blot for PKCγ\",\n      \"journal\": \"Zeitschrift fur Naturforschung. C, Journal of biosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method, pathway placement based on correlation of PKCγ levels without direct epistasis\",\n      \"pmids\": [\"22351987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-glycosylation of Sez6 regulates its cell-surface distribution and function; the SC4-7 glycosylation cluster is specifically required for filopodia-like protrusion formation, while removal of SC1-3 or SC4-7 clusters reduces neurite formation. Unglycosylated Sez6 is still transported to the membrane but shows altered distribution.\",\n      \"method\": \"N-glycosylation cluster deletion mutants transfected into Neuro2a cells, cell surface distribution analysis, conditioned medium analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of specific glycosylation sites with functional readouts in neuronal cell line\",\n      \"pmids\": [\"25960298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sez6 is a substrate of BACE1 (β-secretase); BACE1 cleaves the type I transmembrane isoform of Sez6, shedding its extracellular domain from the neuron surface. Enhanced BACE1-cleavage of Sez6 and Sez6L is detected in NPC1-null mouse brains. Sez6 and Sez6L show increased punctate staining within the endolysosomal pathway in NPC1-null neurons, indicating a trafficking defect underlies enhanced BACE1 proteolysis.\",\n      \"method\": \"Immunoblot of BACE1 cleavage products in NPC1-null vs. wild-type mouse brains, immunofluorescence of endolysosomal colocalization in primary cortical neurons\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical detection of cleavage products in vivo and cell-based localization, but mechanism of BACE1 substrate relationship established in prior work\",\n      \"pmids\": [\"29979789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The BACE1-shed extracellular domain of Sez6 is detectable in human cerebrospinal fluid, and Sez6 levels are elevated in CSF of patients with inflammatory pain conditions. Sez6 knockout mice show attenuated pain behaviors after peripheral nerve injury.\",\n      \"method\": \"Western blot of CSF from surgical patients; behavioral analysis of sez6 knockout mice after nerve injury\",\n      \"journal\": \"Pain reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse behavioral phenotype combined with human CSF detection; two orthogonal approaches in one study\",\n      \"pmids\": [\"31041421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sez6 family proteins (Sez6, Sez6L, Sez6L2) collectively regulate dendritic spine structure and density; triple knockout (TKO) mice lacking all three family members show reduced hippocampal spine density and shift toward immature spine morphologies in somatosensory cortex, along with impaired motor learning and cognitive flexibility.\",\n      \"method\": \"Sez6 triple knockout mice, spine morphology analysis, behavioral testing (motor coordination, Morris water maze, working memory)\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean TKO with defined structural and behavioral phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"31711114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sez6, Sez6L, and Sez6L2 function as complement inhibitors: they inhibit C3b/iC3b opsonization by the classical and alternative complement pathways. Using Sez6L2 as representative, the family accelerates dissociation of C3 convertases and acts as a cofactor for Factor I to facilitate cleavage of C3b (but not C4b).\",\n      \"method\": \"Complement inhibition assays (classical and alternative pathway opsonization), C3 convertase decay assay, Factor I cofactor assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple in vitro biochemical assays with reconstitution of complement pathway steps and defined mechanistic dissection\",\n      \"pmids\": [\"33936031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In 5xFAD Alzheimer's disease mouse brains, BACE1 accumulation in peri-plaque regions does not enhance proteolytic cleavage of Sez6 or Sez6L, but both proteins show altered distribution in areas surrounding Aβ plaques, distinct from APP/BACE1/LAMP1 localization.\",\n      \"method\": \"Western blot for Sez6/Sez6L cleavage products in 5xFAD brains, immunofluorescence localization relative to Aβ plaques\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical and immunofluorescence in validated AD mouse model, but single lab\",\n      \"pmids\": [\"35998821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sez6 alternative splicing produces three isoforms (dominant transmembrane, and two recessive isoforms including a secreted form) with brain-area-specific splicing patterns; the striatum shows a characteristic recessive isoform pattern. Neuronal activation by convulsant drug increases recessive isoforms similarly to the dominant isoform in cultured cortical neurons.\",\n      \"method\": \"qPCR of isoform-specific primers across brain regions and cultured cortical neurons under convulsant stimulation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression-level isoform analysis without functional readout of specific isoform activities\",\n      \"pmids\": [\"36368155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEZ6 is rapidly internalized upon antibody binding to its extracellular domain on the cell surface, enabling antibody-drug conjugate payload delivery in SCLC cells.\",\n      \"method\": \"Antibody internalization assay in SEZ6-expressing SCLC cell lines, in vitro and in vivo ADC efficacy\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct internalization assay combined with in vitro and in vivo efficacy readout\",\n      \"pmids\": [\"35642431\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEZ6 is a type I transmembrane glycoprotein with CCP/SCR and CUB domains that functions as a complement inhibitor (accelerating C3 convertase decay and acting as a Factor I cofactor for C3b cleavage), a BACE1 substrate whose shedding releases a soluble ectodomain, and a regulator of neuronal dendritic arborization and spine density where membrane-bound and secreted isoforms exert opposing effects on branching, collectively shaping excitatory synaptic connectivity in the developing brain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEZ6 is a type I transmembrane glycoprotein that regulates dendritic arborization, spine density, and excitatory synaptic connectivity in the developing brain while also functioning as a complement pathway inhibitor. Its ectodomain contains five CCP/SCR domains and two CUB-like repeats; alternative splicing generates membrane-bound and secreted isoforms that exert opposing effects on dendritic branching—membrane-bound Sez6 suppresses branching whereas secreted Sez6 promotes it—and loss of Sez6 in knockout mice results in excess short dendrites, reduced spine density, diminished PSD-95 puncta, and attenuated excitatory postsynaptic responses [PMID:18031681, PMID:31711114]. SEZ6 family members inhibit C3b opsonization by accelerating C3 convertase decay and serving as cofactors for Factor I–mediated cleavage of C3b, establishing a direct role in complement regulation at the neuronal surface [PMID:33936031]. The transmembrane isoform is a BACE1 substrate whose ectodomain shedding releases a soluble fragment detectable in cerebrospinal fluid, and N-glycosylation of specific CCP clusters governs cell-surface distribution and neurite-promoting activity [PMID:29979789, PMID:25960298].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning of SEZ6 revealed a novel transmembrane architecture with complement-related CCP/SCR and CUB domains, establishing that a seizure-responsive gene encodes a protein with potential complement-signaling and cell-recognition functions.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and domain prediction from seizure-induced brain libraries; in vitro translation and immunoblot confirmed glycosylation and multiple isoforms including a secreted form\",\n      \"pmids\": [\"7723619\", \"7488116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional assay for complement binding or cell recognition\",\n        \"Ligand or binding partner unknown\",\n        \"Isoform-specific functions not tested\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout mouse studies answered the question of SEZ6's neuronal function, demonstrating that it is required for normal dendritic arborization, spine density, and excitatory synaptic connectivity, with membrane-bound and secreted isoforms exerting opposing effects on branching.\",\n      \"evidence\": \"Sez6 null mutant mice, isoform-specific rescue in cultured KO neurons, electrophysiology, PSD-95 immunostaining\",\n      \"pmids\": [\"18031681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which membrane-bound Sez6 inhibits branching is unknown\",\n        \"Direct binding partners mediating dendritic effects not identified\",\n        \"Signaling pathways downstream of Sez6 at the membrane not defined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Developmental relocalization of Sez6 protein from dendrites to the perisomatic region after postnatal day 10 indicated a temporal shift in function, while a separate study linked Sez6 to PKCγ-dependent neurite outgrowth.\",\n      \"evidence\": \"Immunohistochemistry with validated antibody across postnatal time points; shRNA knockdown in PC12 cells with PKCγ Western blot\",\n      \"pmids\": [\"21334315\", \"22351987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of relocalization not directly tested\",\n        \"PKCγ link based on correlation without direct epistasis experiments\",\n        \"Whether PKCγ pathway operates in primary neurons is untested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Site-directed mutagenesis of N-glycosylation clusters showed that specific glycan modifications regulate Sez6 cell-surface distribution and filopodia formation, providing the first post-translational mechanism controlling its activity.\",\n      \"evidence\": \"Glycosylation cluster deletion mutants in Neuro2a cells with surface distribution and morphology analysis\",\n      \"pmids\": [\"25960298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not validated in primary neurons\",\n        \"How glycosylation affects ligand binding or complement function unknown\",\n        \"Whether glycosylation modulates BACE1 cleavage site accessibility not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of SEZ6 as a BACE1 substrate answered how its ectodomain is shed, and revealed that endolysosomal trafficking defects (as in NPC1 deficiency) enhance BACE1-mediated cleavage.\",\n      \"evidence\": \"Immunoblot of BACE1 cleavage products in NPC1-null versus wild-type mouse brains; endolysosomal colocalization in primary cortical neurons\",\n      \"pmids\": [\"29979789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"BACE1 cleavage site on Sez6 not mapped\",\n        \"Functional consequence of enhanced shedding in NPC1 disease context not determined\",\n        \"Whether soluble ectodomain retains complement-inhibitory activity unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Detection of shed Sez6 ectodomain in human CSF and attenuated pain behavior in Sez6 knockout mice extended SEZ6 function beyond dendritic development to peripheral nociceptive signaling.\",\n      \"evidence\": \"Western blot of CSF from surgical patients; behavioral analysis of Sez6 knockout mice after peripheral nerve injury\",\n      \"pmids\": [\"31041421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking Sez6 to pain signaling not identified\",\n        \"Whether CSF Sez6 is functionally active or a degradation product unknown\",\n        \"Cell types contributing to CSF Sez6 not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Triple knockout of all Sez6 family members established that the family collectively and non-redundantly regulates spine density, spine maturation, motor learning, and cognitive flexibility.\",\n      \"evidence\": \"Sez6/Sez6L/Sez6L2 triple knockout mice with spine morphology analysis and behavioral testing\",\n      \"pmids\": [\"31711114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of each family member to spine phenotype not fully dissected\",\n        \"Downstream signaling pathways shared or distinct among family members unknown\",\n        \"Whether complement inhibition contributes to spine phenotypes not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biochemical reconstitution demonstrated that SEZ6 family proteins are bona fide complement inhibitors that accelerate C3 convertase decay and serve as Factor I cofactors for C3b cleavage, finally assigning a molecular activity to the CCP domains.\",\n      \"evidence\": \"Classical and alternative pathway opsonization assays, C3 convertase decay acceleration assay, Factor I cofactor assay with purified components\",\n      \"pmids\": [\"33936031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether complement inhibition occurs in vivo on neuronal surfaces not shown\",\n        \"Relative potency of Sez6 versus Sez6L2 in complement assays not directly compared\",\n        \"Structural basis for C3b selectivity over C4b unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Studies in AD mouse models, isoform splicing analysis, and antibody-drug conjugate work collectively refined the understanding of Sez6 processing and trafficking: Sez6 shows altered peri-plaque distribution without enhanced cleavage in 5xFAD mice, brain-region-specific alternative splicing, and efficient internalization from the cell surface upon antibody binding.\",\n      \"evidence\": \"Western blot and immunofluorescence in 5xFAD brains; qPCR of isoform-specific primers across brain regions; antibody internalization assays in SCLC cell lines with in vivo ADC efficacy\",\n      \"pmids\": [\"35998821\", \"36368155\", \"35642431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of Sez6 redistribution around amyloid plaques not defined\",\n        \"Functional significance of brain-region-specific splicing patterns untested\",\n        \"Internalization pathway and endosomal routing upon antibody binding not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions remain: what are the direct binding partners through which membrane-bound Sez6 regulates dendritic branching and spine density, whether complement inhibition by Sez6 at the neuronal surface contributes to synapse protection in vivo, and what the structural basis is for isoform-specific opposing functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct neuronal binding partner identified for dendritic phenotype\",\n        \"In vivo complement inhibition at synapses not demonstrated\",\n        \"No structural model of Sez6 ectodomain exists\",\n        \"Relationship between BACE1 shedding and complement-inhibitory function not tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [10]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0, 2, 4, 6, 13]\n      },\n      {\n        \"term_id\": \"GO:0005576\",\n        \"supporting_discovery_ids\": [1, 8]\n      },\n      {\n        \"term_id\": \"GO:0005768\",\n        \"supporting_discovery_ids\": [7]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [10]\n      },\n      {\n        \"term_id\": \"R-HSA-1266738\",\n        \"supporting_discovery_ids\": [2, 3, 9]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BACE1\",\n      \"CFI\",\n      \"C3b\",\n      \"SEZ6L\",\n      \"SEZ6L2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}