Person: Kim, Chun-Hyung
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Kim
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Chun-Hyung
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Kim, Chun-Hyung
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Publication The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease(BioMed Central, 2015) Mata, Ignacio F.; Jang, Yongwoo; Kim, Chun-Hyung; Hanna, David S.; Dorschner, Michael O.; Samii, Ali; Agarwal, Pinky; Roberts, John W.; Klepitskaya, Olga; Shprecher, David R.; Chung, Kathryn A.; Factor, Stewart A.; Espay, Alberto J.; Revilla, Fredy J.; Higgins, Donald S.; Litvan, Irene; Leverenz, James B.; Yearout, Dora; Inca-Martinez, Miguel; Martinez, Erica; Thompson, Tiffany R.; Cholerton, Brenna A.; Hu, Shu-Ching; Edwards, Karen L.; Kim, Kwang-Soo; Zabetian, Cyrus P.Objective: To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). Methods: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users.Publication Altered expression of norepinephrine transporter and norepinephrine in human placenta cause pre-eclampsia through regulated trophoblast invasion(The Korean Society for Reproductive Medicine, 2013) Na, Kyu-Hwan; Choi, Jong Ho; Kim, Chun-Hyung; Kim, Kwang-Soo; Kim, Gi JinObjective: We investigated the norepinephrine transporter (NET) expression in normal and pre-eclamptic placentas and analyzed the invasion activity of trophoblastic cells based on norepinephrine (NE)-NET regulation. Methods: NET and NE expression levels were examined by western blot and enzyme-linked immunosorbent assay, respectively. Trophoblast invasion activity, depending on NE-NET regulation, was determined by NET-small interfering RNA (siRNA) and NET transfection into the human extravillous trophoblast cells with or without NE treatment and invasion rates were analyzed by zymography and an invasion assay. Results: NET mRNA was expressed at a low level in pre-eclamptic placentas compared with normal placentas and NE concentration in maternal plasma increased significantly in pre-eclamptic women compared to normal pregnant women (p<0.05). NET gene upregulation and NE treatment stimulated trophoblast cell invasion up to 2.5-fold (p<0.05) by stimulating matrix metalloproteinase-9 activity via the phosphoinositol-3-kinase/AKT signaling pathway, whereas NET-siRNA with NE treatment reduced invasion rates. Conclusion: NET expression is reduced by inadequate regulation of NE levels during placental development. This suggests that a complementary balance between NET and NE regulates trophoblast cell invasion activities during placental development.Publication Direct Reprogramming of Rat Neural Precursor Cells and Fibroblasts into Pluripotent Stem Cells(Public Library of Science, 2010) Kang, Hoon-Chul; Yang, Eungi; Park, Kyung-Soon; Lee, Kyung-Ah; Hwang, Dong-Youn; Lanza, Robert; Reh, Thomas A.; Chang, Mi-Yoon; Kim, Chun-Hyung; Kim, Dohoon; Moon, Jung-Il; Ko, Sanghyeok; Park, Junpil; Chung, Young; Kim, Kwang-SooBackground: Given the usefulness of rats as an experimental system, an efficient method for generating rat induced pluripotent stem (iPS) cells would provide researchers with a powerful tool for studying human physiology and disease. Here, we report direct reprogramming of rat neural precursor (NP) cells and rat embryonic fibroblasts (REF) into iPS cells by retroviral transduction using either three (Oct3/4, Sox2, and Klf4), four (Oct3/4, Sox2, Klf4, and c-Myc), or five (Oct3/4, Sox2, Klf4, c-Myc, and Nanog) genes. Methodology and Principal Findings: iPS cells were generated from both NP and REF using only three (Oct3/4, Sox2, and Klf4) genes without c-Myc. Two factors were found to be critical for efficient derivation and maintenance of rat iPS cells: the use of rat instead of mouse feeders, and the use of small molecules specifically inhibiting mitogen-activated protein kinase and glycogen synthase kinase 3 pathways. In contrast, introduction of embryonic stem cell (ESC) extracts induced partial reprogramming, but failed to generate iPS cells. However, when combined with retroviral transduction, this method generated iPS cells with significantly higher efficiency. Morphology, gene expression, and epigenetic status confirmed that these rat iPS cells exhibited ESC-like properties, including the ability to differentiate into all three germ layers both in vitro and in teratomas. In particular, we found that these rat iPS cells could differentiate to midbrain-like dopamine neurons with a high efficiency. Conclusions/Significance: Given the usefulness of rats as an experimental system, our optimized method would be useful for generating rat iPS cells from diverse tissues and provide researchers with a powerful tool for studying human physiology and disease.