Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system |
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Authors: | Gyun Jee Song Deepak Prasad Gupta Md Habibur Rahman Hwan Tae Park Imad Al Ghouleh Alessandro Bisello Maan-Gee Lee Jae-Yong Park Hyun Ho Park Jin Hyun Jun Ki Wha Chung Byung-Ok Choi Kyoungho Suk |
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Affiliation: | 1. Department of Medical Science, Institute for Bio-Medical Convergence, Catholic Kwandong University, International St. Mary's Hospital, Incheon, Republic of Korea;2. Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;3. Department of Molecular Neuroscience, College of Medicine, Dong-A University, Busan, Republic of Korea;4. Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;5. Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;6. School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, Republic of Korea;7. College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea;8. Department of Senior Healthcare, BK21 Plus Program, Graduate School of Eulji University, Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam, Republic of Korea;9. Department of Biological Sciences, Kongju National University, Gongju, Republic of Korea;10. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea |
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Abstract: | Finding causative genetic mutations is important in the diagnosis and treatment of hereditary peripheral neuropathies. This study was conducted to find new genes involved in the pathophysiology of hereditary peripheral neuropathy. We identified a new mutation in the EBP50 gene, which is co-segregated with neuropathic phenotypes, including motor and sensory deficit in a family with Charcot–Marie–Tooth disease. EBP50 is known to be important for the formation of microvilli in epithelial cells, and the discovery of this gene mutation allowed us to study the function of EBP50 in the nervous system. EBP50 was strongly expressed in the nodal and paranodal regions of sciatic nerve fibers, where Schwann cell microvilli contact the axolemma, and at the growth tips of primary Schwann cells. In addition, EBP50 expression was decreased in mouse models of peripheral neuropathy. Knockout mice were used to study EBP50 function in the peripheral nervous system. Interestingly motor function deficit and abnormal histology of nerve fibers were observed in EBP50+/− heterozygous mice at 12 months of age, but not 3 months. in vitro studies using Schwann cells showed that NRG1-induced AKT activation and migration were significantly reduced in cells overexpressing the I325V mutant of EBP50 or cells with knocked-down EBP50 expression. In conclusion, we show for the first time that loss of function due to EBP50 gene deficiency or mutation can cause peripheral neuropathy. |
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Keywords: | Charcot–Marie–Tooth disease EBP50 ezrin–radixin–moesin-binding phosphoprotein hereditary peripheral neuropathy mutation Schwann cells |
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