{"id":"811503e1-bdec-5698-8256-cb337b98fe60","stable_key":"649e861b-265a-5912-bc36-3a73e53ef892:l-serine-als-spt-feedback","predicate":"when_variant_escapes","statement":"Four dominantly acting SPTLC1 variants in childhood-onset ALS families disrupted ORMDL-mediated feedback, increasing canonical sphingolipid synthesis.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"6526c664-4753-5382-8bea-444e65ae62a0","mechanism_event_label":"Some variants remove the brake rather than change the preferred amino-acid substrate.","subject":{"id":"da1ba1a7-e457-5459-8e95-a2c405c3330c","slug":"sptlc1","display_name":"Human serine palmitoyltransferase long-chain base subunit 1","entity_type_key":"protein"},"object":{"id":"3347710f-8da9-5149-9a6d-6fc733a97301","slug":"human-ormdl-spt-feedback","display_name":"ORMDL restraint of human serine palmitoyltransferase","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"6526c664-4753-5382-8bea-444e65ae62a0","stable_key":"649e861b-265a-5912-bc36-3a73e53ef892:l-serine-als-spt-feedback-event","event_type":"observed_relationship","label":"Some variants remove the brake rather than change the preferred amino-acid substrate.","description":"Four dominantly acting SPTLC1 variants in childhood-onset ALS families disrupted ORMDL-mediated feedback, increasing canonical sphingolipid synthesis.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"da1ba1a7-e457-5459-8e95-a2c405c3330c","slug":"sptlc1","display_name":"Human serine palmitoyltransferase long-chain base subunit 1","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"3347710f-8da9-5149-9a6d-6fc733a97301","slug":"human-ormdl-spt-feedback","display_name":"ORMDL restraint of human serine palmitoyltransferase","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c882cd0b-9d83-5b07-bd1c-fe4d45657dcb","slug":"l-serine","display_name":"L-Serine","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_access","value_text":"Primary abstract","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human families and engineered cellular lipid-synthesis experiments.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"This molecular subtype differs from HSAN1-associated substrate-switching variants.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"l-serine","display_name":"L-Serine","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"Some variants remove the brake rather than change the preferred amino-acid substrate.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34059824/ · DOI 10.1038/s41591-021-01346-1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; 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