Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation

• Published in: Open biology Vol. 5; no. 6; p. 150047
• Main Authors: Handley, Mark T., Carpanini, Sarah M., Mali, Girish R., Sidjanin, Duska J., Aligianis, Irene A., Jackson, Ian J., FitzPatrick, David R.
• Format: Journal Article
• Language: English
• Published: England The Royal Society 01.06.2015
• Subjects: Abnormalities, Multiple - etiology; Abnormalities, Multiple - metabolism; Abnormalities, Multiple - pathology; Animals; Blotting, Western; Case-Control Studies; Cataract - congenital; Cataract - etiology; Cataract - metabolism; Cataract - pathology; Cells, Cultured; Cornea - abnormalities; Cornea - metabolism; Cornea - pathology; Cytosol - metabolism; Endoplasmic Reticulum - metabolism; Fibroblasts - metabolism; Fibroblasts - pathology; Flow Cytometry; Fluorescent Antibody Technique; Gap; Gef; Gene Expression Regulation; Guanosine Triphosphate - metabolism; HeLa Cells; Humans; Hydrolysis; Hypogonadism - etiology; Hypogonadism - metabolism; Hypogonadism - pathology; Intellectual Disability - etiology; Intellectual Disability - metabolism; Intellectual Disability - pathology; Mice; Mice, Knockout; Microcephaly - etiology; Microcephaly - metabolism; Microcephaly - pathology; Optic Atrophy - etiology; Optic Atrophy - metabolism; Optic Atrophy - pathology; Rab; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; rab1 GTP-Binding Proteins - genetics; rab1 GTP-Binding Proteins - metabolism; Rab18; rab3 GTP-Binding Proteins - genetics; rab3 GTP-Binding Proteins - metabolism; Ras; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RAB18; GEF; Rab; Ras; GAP
• ISSN: 2046-2441; 2046-2441
• DOI: 10.1098/rsob.150047

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.