title: Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation.
abstract: RAB18, RAB3GAP1, RAB3GAP2 and TBC1D20 are each mutated in Warburg Micro syndrome, a rare autosomal recessive multisystem disorder. RAB3GAP1 and RAB3GAP2 form a binary 'RAB3GAP' complex that functions as a guanine-nucleotide exchange factor (GEF) for RAB18, whereas TBC1D20 shows modest RAB18 GTPase-activating (GAP) activity in vitro. Here, we show that in the absence of functional RAB3GAP or TBC1D20, the level, localization and dynamics of cellular RAB18 is altered. In cell lines where TBC1D20 is absent from the endoplasmic reticulum (ER), RAB18 becomes more stably ER-associated and less cytosolic than in control cells. These data suggest that RAB18 is a physiological substrate of TBC1D20 and contribute to a model in which a Rab-GAP can be essential for the activity of a target Rab. Together with previous reports, this indicates that Warburg Micro syndrome can be caused directly by loss of RAB18, or indirectly through loss of RAB18 regulators RAB3GAP or TBC1D20.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK mark.handley@igmm.ed.ac.uk.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Handley
authors.affiliation: Division of Neurobiology, The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Carpanini
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Girish R
authors.initials: GR
authors.lastname: Mali
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Duska J
authors.initials: DJ
authors.lastname: Sidjanin
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Irene A
authors.initials: IA
authors.lastname: Aligianis
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002386:Cataract / Q000151:congenital* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003315:Cornea / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007006:Hypogonadism / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008607:Intellectual Disability / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D009896:Optic Atrophy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020761:rab1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020692:rab3 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C484168:RAB18 protein, human; D012333:RNA, Messenger; C526344:TBC1D20 protein, human; D006160:Guanosine Triphosphate; C580955:RAB3GAP1 protein, human; D020691:rab GTP-Binding Proteins; D020761:rab1 GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins
keywords: GAP; GEF; RAB18; Rab; Ras