A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.
Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals 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 owing to the lack of any robust animal models that phenocopy both the 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 the characteristic ocular features that are associated with WARBM. Additionally, Rab18-mutant cells exhibit an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of cells taken from WARBM individuals, as well as cells taken from individuals 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 caused by 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 nerves in Rab18-mutant mice reveals significant alterations in several core molecular pathways that regulate cytoskeletal dynamics in neurons. The apparent similarities between the WARBM phenotype and the phenotype that we describe here indicate that the Rab18-mutant mouse provides an important platform for investigation of the disease pathogenesis and therapeutic interventions.
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK.
Sarah M
SM
Carpanini
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Lisa
L
McKie
Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Derek
D
Thomson
Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Ann K
AK
Wright
Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Sarah L
SL
Gordon
Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Sarah L
SL
Roche
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Mark T
MT
Handley
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Harris
H
Morrison
Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
David
D
Brownstein
The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK. Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Thomas M
TM
Wishart
Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Michael A
MA
Cousin
Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK. t.gillingwater@ed.ac.uk ian.jackson@igmm.ed.ac.uk.
Thomas H
TH
Gillingwater
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Irene A
IA
Aligianis
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK. t.gillingwater@ed.ac.uk ian.jackson@igmm.ed.ac.uk.
Ian J
IJ
Jackson
D000015:Abnormalities, Multiple / Q000503:physiopathology*; D000818:Animals; D002386:Cataract / Q000151:congenital* / Q000503:physiopathology; D003315:Cornea / Q000002:abnormalities* / Q000503:physiopathology; D003599:Cytoskeleton / Q000502:physiology*; D004195:Disease Models, Animal; D005123:Eye / Q000254:growth & development*; D007006:Hypogonadism / Q000503:physiopathology*; D008607:Intellectual Disability / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology*; D009896:Optic Atrophy / Q000503:physiopathology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
C083879:Rab18 protein, mouse; D020691:rab GTP-Binding Proteins
Cataract; Neurofilament; Warburg Micro syndrome