Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system.,Glia

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Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system.
Glia ( IF 5.4 ) Pub Date : 2020-02-20 , DOI: 10.1002/glia.23805
Gyun Jee Song ₁ , Deepak Prasad Gupta ₂ , Md Habibur Rahman ₂ , Hwan Tae Park ₃ , Imad Al Ghouleh ₄ , Alessandro Bisello ₅ , Maan-Gee Lee ₂ , Jae-Yong Park ₆ , Hyun Ho Park ₇ , Jin Hyun Jun ₈ , Ki Wha Chung ₉ , Byung-Ok Choi ₁₀ , Kyoungho Suk ₂

Affiliation

Department of Medical Science, Institute for Bio-Medical Convergence, Catholic Kwandong University, International St. Mary's Hospital, Incheon, Republic of Korea.
Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Department of Molecular Neuroscience, College of Medicine, Dong-A University, Busan, Republic of Korea.
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, Republic of Korea.
College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
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.
Department of Biological Sciences, Kongju National University, Gongju, Republic of Korea.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

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.

中文翻译：

EBP50 的功能丧失是遗传性周围神经病变的新原因：EBP50 在周围神经系统中起作用。

寻找致病基因突变对于遗传性周围神经病的诊断和治疗非常重要。进行这项研究是为了寻找与遗传性周围神经病的病理生理学有关的新基因。我们在EBP50 中发现了一个新的突变该基因与神经病表型共同分离，包括 Charcot-Marie-Tooth 病家族的运动和感觉缺陷。众所周知，EBP50 对于上皮细胞中微绒毛的形成很重要，这一基因突变的发现使我们能够研究 EBP50 在神经系统中的功能。EBP50 在坐骨神经纤维的结节和副结区（雪旺细胞微绒毛与轴突接触的地方）和原代雪旺细胞的生长尖端强烈表达。此外，EBP50 表达在周围神经病变小鼠模型中降低。敲除小鼠用于研究外周神经系统中的 EBP50 功能。有趣的是，在 EBP50 ^+/-中观察到运动功能缺陷和神经纤维组织学异常12 个月大但不是 3 个月大的杂合子小鼠。使用雪旺氏细胞的体外研究表明，在过表达 EBP50 的 I325V 突变体的细胞或敲低 EBP50 表达的细胞中，NRG1 诱导的 AKT 激活和迁移显着降低。总之，我们首次表明EBP50基因缺陷或突变导致的功能丧失可导致周围神经病变。

更新日期：2020-02-20

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