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Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation. Open Biol 2015 Jun;5(6):150047

Date

06/13/2015

Pubmed ID

26063829

Pubmed Central ID

PMC4632505

DOI

10.1098/rsob.150047

Scopus ID

2-s2.0-84934923305 (requires institutional sign-in at Scopus site)   46 Citations

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.

Author List

Handley MT, Carpanini SM, Mali GR, Sidjanin DJ, Aligianis IA, Jackson IJ, FitzPatrick DR

Author

Danielle Sidjanin Maier PhD, MSN APP Supervisor Inpatient 2 in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Animals
Blotting, Western
Case-Control Studies
Cataract
Cells, Cultured
Cornea
Cytosol
Endoplasmic Reticulum
Fibroblasts
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression Regulation
Guanosine Triphosphate
HeLa Cells
Humans
Hydrolysis
Hypogonadism
Intellectual Disability
Mice
Mice, Knockout
Microcephaly
Optic Atrophy
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
rab GTP-Binding Proteins
rab1 GTP-Binding Proteins
rab3 GTP-Binding Proteins