title: Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy.
abstract: The mechanistic target of rapamycin complex 1 (TORC1) senses nutrient availability to regulate eukaryotic anabolic metabolism. In response to limiting concentrations of amino acids, TORC1 kinase activity is inhibited through the GATOR-1 complex. Mutations in DEPDC5, that encodes one of the components of the GATOR-1 complex, have recently been associated with different forms of focal epilepsy. Here, we investigate the effects of 10 DEPDC5 variants identified in individuals with focal epilepsy and two DEPDC5 variants identified in serous ovarian tumors, on TORC1 signaling and GATOR-1 complex formation. According to our functional assessment, three variants clearly disrupted the DEPDC5-dependent inhibition of TORC1. We did not obtain functional evidence to support pathogenicity in the remaining cases. The observed functional differences between the DEPDC5 variants might underlie some of the clinical differences observed in the individuals carrying the different variants.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: van Kranenburg
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
mesh_terms: D004828:Epilepsies, Partial / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000378:metabolism; D056726:Genetic Association Studies; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; C492816:NPRL2 protein, human; C543618:NPRL3 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C064658:RAG-1 protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: DEPDC5; TORC1 signaling; focal epilepsy; functional studies