title: ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18.
abstract: Mutations in the gene of RAB18, a member of Ras superfamily of small G-proteins, cause Warburg Micro Syndrome (WARBM) which is characterized by defective neurodevelopmental and ophthalmological phenotypes. Despite loss of Rab18 had been reported to induce disruption of the endoplasmic reticulum structure and neuronal cytoskeleton organization, parts of the pathogenic mechanism caused by RAB18 mutation remain unclear. From the N-ethyl-N-nitrosourea (ENU)-induced mutagenesis library, we identified a mouse line whose Rab18 was knocked out. This Rab18(-/-) mouse exhibited stomping gait, smaller testis and eyes, mimicking several features of WARBM. Rab18(-/-) mice were obviously less sensitive to pain and touch than WT mice. Histological examinations on Rab18(-/-) mice revealed progressive axonal degeneration in the optic nerves, dorsal column of the spinal cord and sensory roots of the spinal nerves while the motor roots were spared. All the behavioral and pathological changes that resulted from abnormalities in the sensory axons were prevented by introducing an extra copy of Rab18 transgene in Rab18(-/-) mice. Our results reveal that sensory axonal degeneration is the primary cause of stomping gait and progressive weakness of the hind limbs in Rab18(-/-) mice, and optic nerve degeneration should be the major pathology of progressive optic atrophy in children with WARBM. Our results indicate that the sensory nervous system is more vulnerable to Rab18 deficiency and WARBM is not only a neurodevelopmental but also neurodegenerative disease.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine and Cancer Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Jaw-Ching
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Tsai
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Fang-Shin
authors.initials: FS
authors.lastname: Nian
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Wu
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Lung-Sen
authors.initials: LS
authors.lastname: Kao
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Fann
authors.affiliation: Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Tsai
authors.affiliation: Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ying-Jay
authors.initials: YJ
authors.lastname: Liou
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Chin-Yin
authors.initials: CY
authors.lastname: Tai
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: cjhong007@gmail.com.
authors.forename: Chen-Jee
authors.initials: CJ
authors.lastname: Hong
mesh_terms: D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D002386:Cataract / Q000139:chemically induced / Q000150:complications / Q000151:congenital* / Q000235:genetics; D003315:Cornea / Q000002:abnormalities*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000648:ultrastructure; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005123:Eye / Q000473:pathology; D007006:Hypogonadism / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D008607:Intellectual Disability / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008831:Microcephaly / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D008850:Microphthalmos / Q000209:etiology / Q000235:genetics; D016296:Mutagenesis / Q000187:drug effects*; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology; D009896:Optic Atrophy / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D009901:Optic Nerve Diseases / Q000209:etiology / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects; D017384:Sequence Deletion / Q000235:genetics*; D013737:Testis / Q000473:pathology; D055698:Touch Perception / Q000187:drug effects / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C083879:Rab18 protein, mouse; D020691:rab GTP-Binding Proteins; D005038:Ethylnitrosourea
keywords: Axonal degeneration; Rab18; Sensory; Stomping gait; Warburg Micro Syndrome