{"id":"ea6aab0e-2348-50ec-8933-e3a62a4540b8","stable_key":"1deb434a-3547-51a0-a038-87b1ce79ec38:vd-act-megalin-knockout-loss","predicate":"deletion_increases","statement":"Megalin-null mice failed to retrieve filtered calcifediol and lost the vitamin D precursor in urine.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"309b81c5-8bff-5883-a86f-7ea52092fac0","mechanism_event_label":"A broken kidney uptake receptor wastes vitamin D precursor.","subject":{"id":"e14673e3-7ff6-5835-afa1-3fe37c024f2d","slug":"mouse-lrp2-gene","display_name":"Mouse Lrp2 gene","entity_type_key":"gene"},"object":{"id":"b51960e5-4277-547b-9871-6f7741ef8516","slug":"urinary-calcifediol-loss","display_name":"Urinary loss of calcifediol","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"309b81c5-8bff-5883-a86f-7ea52092fac0","stable_key":"1deb434a-3547-51a0-a038-87b1ce79ec38:vd-act-megalin-knockout-loss-event","event_type":"biochemical_relationship","label":"A broken kidney uptake receptor wastes vitamin D precursor.","description":"Megalin-null mice failed to retrieve filtered calcifediol and lost the vitamin D precursor in urine.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"249ecc7c-b115-508f-acda-94c954e5cd2b","slug":"mouse-lrp2","display_name":"Mouse megalin / Lrp2","entity_type_key":"protein"},"role":"missing_receptor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"0c858f70-5b07-5db5-8494-bfe3d8733b34","slug":"mouse-gc","display_name":"Mouse vitamin D-binding protein / Gc","entity_type_key":"protein"},"role":"carrier","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"6bd73bd2-1f0a-5caa-ba69-7ce1b75364bb","slug":"calcifediol","display_name":"Calcifediol / 25-hydroxyvitamin D3","entity_type_key":"small_molecule"},"role":"lost_cargo","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"e14673e3-7ff6-5835-afa1-3fe37c024f2d","slug":"mouse-lrp2-gene","display_name":"Mouse Lrp2 gene","entity_type_key":"gene"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"b51960e5-4277-547b-9871-6f7741ef8516","slug":"urinary-calcifediol-loss","display_name":"Urinary loss of calcifediol","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_location","value_text":"Primary abstract, receptor-mediated uptake and knockout phenotype.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Targeted megalin knockout versus controls","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Lrp2 gene disruption; no dietary restriction inferred.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The knockout affects other filtered ligands too; it is machinery impairment.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient","value_text":"Vitamin D2 and D3","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-d","display_name":"Vitamin D2 and D3","entity_type_key":"chemical_species"}},{"dimension":"nutrient_topic","value_text":"Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-d","display_name":"Vitamin D2 and D3","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Mus musculus","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A broken kidney uptake receptor wastes vitamin D precursor.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[nykjaer1999] An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. (1999). https://pubmed.ncbi.nlm.nih.gov/10052453/ DOI: 10.1016/s0092-8674(00)80655-8","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"kidney and urine","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"0504fe40-4e48-5873-9838-31031246a03f","evidence_kind":"source_excerpt","locator":"Lines 242-255","start_line":242,"end_line":255,"excerpt":"### vd-act-megalin-knockout-loss\nMegalin-null mice failed to retrieve filtered calcifediol and lost the vitamin D precursor in urine.\nCondition category: machinery_impairment\nnutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A broken kidney uptake receptor wastes vitamin D precursor.\norganism: Mus musculus\ntissue_or_cell_type: kidney and urine\nexperimental_model: Targeted megalin knockout versus controls\nlimitations: The knockout affects other filtered ligands too; it is machinery impairment.\nexposure: Lrp2 gene disruption; no dietary restriction inferred.\ncross_nutrient: false\nevidence_location: Primary abstract, receptor-mediated uptake and knockout phenotype.\nnutrient: Vitamin D2 and D3\n[nykjaer1999] An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. 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