{"gene":"PLXNA3","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2021,"finding":"Loss-of-function missense variants in PLXNA3 (encoding plexin-A3, the receptor for semaphorin-3F) were identified in patients with idiopathic hypogonadotropic hypogonadism (IHH). Functional assays in transiently transfected HEK293T cells demonstrated that the identified variants were deleterious. Fluorescent immunohistochemistry showed that PLXNA3 is expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve, and PLXNA1-A3 are expressed in early migratory GnRH neurons, placing PLXNA3 in the SEMA3F signaling pathway required for GnRH neuron guidance and olfactory/vomeronasal nerve fiber development.","method":"Exome sequencing of 216 IHH patients; transient transfection of HEK293T cells with WT or variant plasmids for functional assays; fluorescent immunohistochemistry on human fetal nasal region and nasal/forebrain junction tissue","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays plus direct localization by IHC in human fetal tissue, single lab, two orthogonal methods; full reconstitution or structural data not reported","pmids":["33495532"],"is_preprint":false}],"current_model":"PLXNA3 (plexin-A3) acts as a receptor for semaphorin-3F (SEMA3F) and is expressed in early migratory GnRH neurons and along olfactory/vomeronasal nerve fibers; loss-of-function variants in PLXNA3 cause idiopathic hypogonadotropic hypogonadism by disrupting SEMA3F-mediated guidance of GnRH neurons and olfactory/vomeronasal nerve fibers during human fetal development."},"narrative":{"mechanistic_narrative":"PLXNA3 encodes plexin-A3, a receptor for semaphorin-3F (SEMA3F) that functions in the guidance of GnRH neurons and olfactory/vomeronasal nerve fibers during human fetal development [PMID:33495532]. PLXNA3 is expressed along the olfactory nerve and the intracranial projection of the vomeronasal/terminal nerve, and together with PLXNA1 and PLXNA2 is present in early migratory GnRH neurons, positioning it within the SEMA3F signaling pathway that directs these cells [PMID:33495532]. Loss-of-function missense variants in PLXNA3 cause idiopathic hypogonadotropic hypogonadism, consistent with disrupted SEMA3F-mediated guidance of GnRH neurons and olfactory/vomeronasal fibers [PMID:33495532]. Beyond this receptor role and disease association, no further mechanistic detail — including downstream signaling, co-receptor requirements, or structural basis of ligand binding — has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Established that PLXNA3 is a disease gene for idiopathic hypogonadotropic hypogonadism and placed it mechanistically in the SEMA3F guidance pathway for GnRH neurons and olfactory/vomeronasal nerve fibers.","evidence":"Exome sequencing of 216 IHH patients with cell-based functional assays of variants in HEK293T cells and fluorescent immunohistochemistry of human fetal nasal/forebrain tissue","pmids":["33495532"],"confidence":"Medium","gaps":["No reconstitution of SEMA3F binding or downstream signaling by PLXNA3 reported","No structural data on the receptor or its variants","Relative contributions of PLXNA1/A2/A3 to GnRH neuron guidance not dissected"]},{"year":null,"claim":"How PLXNA3 transduces SEMA3F signaling at the molecular level and which co-receptors and downstream effectors mediate GnRH neuron and nerve fiber guidance remains unresolved.","evidence":"No further experimental characterization in the available corpus","pmids":[],"confidence":"Medium","gaps":["Downstream signaling effectors unidentified","Co-receptor (e.g. neuropilin) requirements not tested in this corpus","In vivo guidance mechanism not directly demonstrated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["SEMA3F"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51805","full_name":"Plexin-A3","aliases":["Plexin-4","Semaphorin receptor SEX"],"length_aa":1871,"mass_kda":207.7,"function":"Coreceptor for SEMA3A and SEMA3F. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance in the developing nervous system. Regulates the migration of sympathetic neurons, but not of neural crest precursors. Required for normal dendrite spine morphology in pyramidal neurons. May play a role in regulating semaphorin-mediated programmed cell death in the developing nervous system. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P51805/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNA3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNA3","total_profiled":1310},"omim":[{"mim_id":"601581","title":"NEURONAL CELL ADHESION MOLECULE; NRCAM","url":"https://www.omim.org/entry/601581"},{"mim_id":"300022","title":"PLEXIN A3; PLXNA3","url":"https://www.omim.org/entry/300022"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Functional assays in transiently transfected HEK293T cells demonstrated that the identified variants were deleterious. Fluorescent immunohistochemistry showed that PLXNA3 is expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve, and PLXNA1-A3 are expressed in early migratory GnRH neurons, placing PLXNA3 in the SEMA3F signaling pathway required for GnRH neuron guidance and olfactory/vomeronasal nerve fiber development.\",\n      \"method\": \"Exome sequencing of 216 IHH patients; transient transfection of HEK293T cells with WT or variant plasmids for functional assays; fluorescent immunohistochemistry on human fetal nasal region and nasal/forebrain junction tissue\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays plus direct localization by IHC in human fetal tissue, single lab, two orthogonal methods; full reconstitution or structural data not reported\",\n      \"pmids\": [\"33495532\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNA3 (plexin-A3) acts as a receptor for semaphorin-3F (SEMA3F) and is expressed in early migratory GnRH neurons and along olfactory/vomeronasal nerve fibers; loss-of-function variants in PLXNA3 cause idiopathic hypogonadotropic hypogonadism by disrupting SEMA3F-mediated guidance of GnRH neurons and olfactory/vomeronasal nerve fibers during human fetal development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNA3 encodes plexin-A3, a receptor for semaphorin-3F (SEMA3F) that functions in the guidance of GnRH neurons and olfactory/vomeronasal nerve fibers during human fetal development [#0]. PLXNA3 is expressed along the olfactory nerve and the intracranial projection of the vomeronasal/terminal nerve, and together with PLXNA1 and PLXNA2 is present in early migratory GnRH neurons, positioning it within the SEMA3F signaling pathway that directs these cells [#0]. Loss-of-function missense variants in PLXNA3 cause idiopathic hypogonadotropic hypogonadism, consistent with disrupted SEMA3F-mediated guidance of GnRH neurons and olfactory/vomeronasal fibers [#0]. Beyond this receptor role and disease association, no further mechanistic detail — including downstream signaling, co-receptor requirements, or structural basis of ligand binding — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that PLXNA3 is a disease gene for idiopathic hypogonadotropic hypogonadism and placed it mechanistically in the SEMA3F guidance pathway for GnRH neurons and olfactory/vomeronasal nerve fibers.\",\n      \"evidence\": \"Exome sequencing of 216 IHH patients with cell-based functional assays of variants in HEK293T cells and fluorescent immunohistochemistry of human fetal nasal/forebrain tissue\",\n      \"pmids\": [\"33495532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reconstitution of SEMA3F binding or downstream signaling by PLXNA3 reported\",\n        \"No structural data on the receptor or its variants\",\n        \"Relative contributions of PLXNA1/A2/A3 to GnRH neuron guidance not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLXNA3 transduces SEMA3F signaling at the molecular level and which co-receptors and downstream effectors mediate GnRH neuron and nerve fiber guidance remains unresolved.\",\n      \"evidence\": \"No further experimental characterization in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling effectors unidentified\",\n        \"Co-receptor (e.g. neuropilin) requirements not tested in this corpus\",\n        \"In vivo guidance mechanism not directly demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"SEMA3F\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}