guanosine-triphosphate and Microcephaly

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.

Topics: 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; rab GTP-Binding Proteins; rab1 GTP-Binding Proteins; rab3 GTP-Binding Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Although most components of the mitochondrial translation apparatus are encoded by nuclear genes, all known molecular defects associated with impaired mitochondrial translation are due to mutations in mitochondrial DNA. We investigated two siblings with a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)-encoded subunits, and progressive hepatoencephalopathy. We mapped the defective gene to a region on chromosome 3q containing elongation factor G1 (EFG1), which encodes a mitochondrial translation factor. Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)-binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation.

Topics: Chromosomes, Human, Pair 3; DNA, Complementary; DNA, Mitochondrial; Electron Transport Chain Complex Proteins; Female; Fibroblasts; Guanosine Triphosphate; Humans; Infant; Infant, Newborn; Liver Failure; Male; Microcephaly; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Peptide Elongation Factor G; Protein Biosynthesis; Sequence Analysis, DNA