A novel mouse model of Warburg Micro Syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton

• Published in: Disease models & mechanisms Vol. 7; no. 6; pp. 711 - 722
• Main Authors: Carpanini, Sarah M., McKie, Lisa, Thomson, Derek, Wright, Ann K., Gordon, Sarah L., Roche, Sarah L., Handley, Mark T., Morrison, Harris, Brownstein, David, Wishart, Thomas M., Cousin, Michael A., Gillingwater, Thomas H., Aligianis, Irene A., Jackson, Ian J.
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.06.2014; The Company of Biologists Limited; The Company of Biologists
• Subjects: Abnormalities, Multiple - physiopathology; Animals; Blindness; Cataract; Cataract - congenital; Cataract - physiopathology; Cataracts; Congenital diseases; Cornea - abnormalities; Cornea - physiopathology; Cytoskeleton; Cytoskeleton - physiology; Disease Models, Animal; Endoplasmic reticulum; Eye - growth & development; Fibroblasts; Genotype & phenotype; Hypogonadism - physiopathology; Intellectual Disability - physiopathology; Lipids; Mice; Mice, Knockout; Microcephaly - physiopathology; Mutation; Nervous system; Neurofilament; Neurons - physiology; Optic Atrophy - physiopathology; Pathogenesis; Proteins; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - physiology; Rodents; Stem cells; Warburg Micro syndrome; Warburg Micro syndrome; Cataract; Neurofilament
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.015222

Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Patients with WARBM present with a range of clinical symptoms including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely due to the lack of any robust animal models phenocopying both ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18 mutant mouse model of WARBM. Rab18 mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating characteristic ocular features associated with WARBM. In addition, Rab18 mutant cells have an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of WARBM patient cells, as well as cells from patients with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18 mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are most likely not due to gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerve in Rab18 mutant mice reveals significant alterations in several core molecular pathways regulating cytoskeletal dynamics in neurons. The clear similarities between WARBM and the phenotype we describe indicate that the Rab18 mutant mouse provides an important platform for investigating the disease pathogenesis and therapeutic interventions.