Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation.
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.
['Handley|Mark T|MT|', 'Carpanini|Sarah M|SM|', 'Mali|Girish R|GR|', 'Sidjanin|Duska J|DJ|', 'Aligianis|Irene A|IA|', 'Jackson|Ian J|IJ|', 'FitzPatrick|David R|DR|']
D000015:Abnormalities, Multiple D000818:Animals D015153:Blotting, Western D016022:Case-Control Studies D002386:Cataract D002478:Cells, Cultured D003315:Cornea D003600:Cytosol D004721:Endoplasmic Reticulum D005347:Fibroblasts D005434:Flow Cytometry D005455:Fluorescent Antibody Technique D005786:Gene Expression Regulation D006160:Guanosine Triphosphate D006367:HeLa Cells D006801:Humans D006868:Hydrolysis D007006:Hypogonadism D008607:Intellectual Disability D051379:Mice D018345:Mice, Knockout D008831:Microcephaly D009896:Optic Atrophy D012333:RNA, Messenger D060888:Real-Time Polymerase Chain Reaction D020133:Reverse Transcriptase Polymerase Chain Reaction D020691:rab GTP-Binding Proteins D020761:rab1 GTP-Binding Proteins D020692:rab3 GTP-Binding Proteins
RAB18 GEF GAP Rab Ras