[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Cheng, Chih-Ya; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
Wu, Jaw-Ching; 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
Tsai, Jin-Wu; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Brain Research Center, National Yang-Ming University, Taipei, Taiwan
Nian, Fang-Shin ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
Wu, Pei-Chun; Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Kao, Lung-Sen; Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Fann, Ming-Ji; Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Tsai, Shih-Jen; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
Liou, Ying-Jay; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
Tai, Chin-Yin; Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan
Hong, Chen-Jee; 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
Language :
English
Title :
ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18.
This work was supported by grants from the National Science Council Taiwan (NSC 102-2314-B-075-005-MY3 ), the Taipei Veterans General Hospital ( V103E9-004 and V102C-173 ), and the Ministry of Education Taiwan , Aim for the Top University Plan ( 104AC-B6 ).
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