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1. Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases

Author

Tian, Chi, Zhang, Yuntian, Tong, Yihan, Kock, Kian Hong, Sim, Donald Yuhui, Liu, Fei, Dong, Jiaqi, Jing, Zhixuan, Wang, Wenjing, Gao, Junbin, Tan, Le Min, Han, Kyung Yeon, Tomofuji, Yoshihiko, Nakano, Masahiro, Buyamin, Eliora Violain, Sonthalia, Radhika, Ando, Yoshinari, Hatano, Hiroaki, Sonehara, Kyuto, Jin, Xin, Loh, Marie, Chambers, John, Hon, Chung-Chau, Choi, Murim, Park, Jong-Eun, Ishigaki, Kazuyoshi, Okamura, Tomohisa, Fujio, Keishi, Okada, Yukinori, Park, Woong-Yang, Shin, Jay W., Roca, Xavier, Prabhakar, Shyam, and Liu, Boxiang

Published
2024
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6. Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation

Author

Accogli, Andrea, Shakya, Saurabh, Yang, Taewoo, Insinna, Christine, Kim, Soo Yeon, Bell, David, Butov, Kirill R., Severino, Mariasavina, Niceta, Marcello, Scala, Marcello, Lee, Hyun Sik, Yoo, Taekyeong, Stauffer, Jimmy, Zhao, Huijie, Fiorillo, Chiara, Pedemonte, Marina, Diana, Maria C., Baldassari, Simona, Zakharova, Viktoria, Shcherbina, Anna, Rodina, Yulia, Fagerberg, Christina, Roos, Laura Sønderberg, Wierzba, Jolanta, Dobosz, Artur, Gerard, Amanda, Potocki, Lorraine, Rosenfeld, Jill A., Lalani, Seema R., Scott, Tiana M., Scott, Daryl, Azamian, Mahshid S., Louie, Raymond, Moore, Hannah W., Champaigne, Neena L., Hollingsworth, Grace, Torella, Annalaura, Nigro, Vincenzo, Ploski, Rafal, Salpietro, Vincenzo, Zara, Federico, Pizzi, Simone, Chillemi, Giovanni, Ognibene, Marzia, Cooney, Erin, Do, Jenny, Linnemann, Anders, Larsen, Martin J., Specht, Suzanne, Walters, Kylie J., Choi, Hee-Jung, Choi, Murim, Tartaglia, Marco, Youkharibache, Phillippe, Chae, Jong-Hee, Capra, Valeria, Park, Sung-Gyoo, and Westlake, Christopher J.

Published
2024
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7. Quantification of escape from X chromosome inactivation with single-cell omics data reveals heterogeneity across cell types and tissues

Author

Charoensawan, Varodom, Hon, Chung-Chau, Majumder, Partha P., Matangkasombut, Ponpan, Park, Woong-Yang, Prabhakar, Shyam, Shin, Jay W., Carninci, Piero, Chambers, John C., Loh, Marie, Pithukpakorn, Manop, Suktitipat, Bhoom, Yamamoto, Kazuhiko, Rajagopalan, Deepa, Rayan, Nirmala Arul, Sankaran, Shvetha, Chantaraamporn, Juthamard, Chatterjee, Ankita, Ghosh, Supratim, Han, Kyung Yeon, Jevapatarakul, Damita, Nguantad, Sarintip, Sarkar, Sumanta, Thungsatianpun, Narita, Abe, Mai, Furukawa, Seiko, Inoue, Gyo, Myouzen, Keiko, Oh, Jin-Mi, Suzuki, Akari, Ando, Yoshinari, Kojima, Miki, Kouno, Tsukasa, Lim, Jinyeong, Maitra, Arindam, Tan, Le Min, Venkatesh, Prasanna Nori, Choi, Murim, Park, Jong-Eun, Buyamin, Eliora Violain, Kock, Kian Hong, Xuan Lin, Quy Xiao, Moody, Jonathan, Sonthalia, Radhika, Ishigaki, Kazuyoshi, Nakano, Masahiro, Okada, Yukinori, Tomofuji, Yoshihiko, Ho Namkoong, Edahiro, Ryuya, Takano, Tomomi, Nishihara, Hiroshi, Shirai, Yuya, Sonehara, Kyuto, Tanaka, Hiromu, Azekawa, Shuhei, Mikami, Yohei, Lee, Ho, Hasegawa, Takanori, Okudela, Koji, Okuzaki, Daisuke, Motooka, Daisuke, Kanai, Masahiro, Naito, Tatsuhiko, Yamamoto, Kenichi, Wang, Qingbo S., Saiki, Ryunosuke, Ishihara, Rino, Matsubara, Yuta, Hamamoto, Junko, Hayashi, Hiroyuki, Yoshimura, Yukihiro, Tachikawa, Natsuo, Yanagita, Emmy, Hyugaji, Takayoshi, Shimizu, Eigo, Katayama, Kotoe, Kato, Yasuhiro, Morita, Takayoshi, Takahashi, Kazuhisa, Harada, Norihiro, Naito, Toshio, Hiki, Makoto, Matsushita, Yasushi, Takagi, Haruhi, Aoki, Ryousuke, Nakamura, Ai, Harada, Sonoko, Sasano, Hitoshi, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Morita, Atsuho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Uchida, Sho, Uno, Shunsuke, Nishimura, Tomoyasu, Ishiguro, Takashi, Isono, Taisuke, Shibata, Shun, Matsui, Yuma, Hosoda, Chiaki, Takano, Kenji, Nishida, Takashi, Kobayashi, Yoichi, Takaku, Yotaro, Takayanagi, Noboru, Ueda, Soichiro, Tada, Ai, Miyawaki, Masayoshi, Yamamoto, Masaomi, Yoshida, Eriko, Hayashi, Reina, Nagasaka, Tomoki, Arai, Sawako, Kaneko, Yutaro, Sasaki, Kana, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Takahashi, Kunihiko, Anzai, Tatsuhiko, Ito, Satoshi, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro Tani, Nakajima, Jun, Nakano, Yasushi, Nakajima, Yukiko, Anan, Ryusuke, Arai, Ryosuke, Kurihara, Yuko, Harada, Yuko, Nishio, Kazumi, Ueda, Tetsuya, Azuma, Masanori, Saito, Ryuichi, Sado, Toshikatsu, Miyazaki, Yoshimune, Sato, Ryuichi, Haruta, Yuki, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Kimura, Tomoki, Sato, Tomonori, Takei, Reoto, Hagimoto, Satoshi, Noguchi, Yoichiro, Yamano, Yasuhiko, Sasano, Hajime, Ota, Sho, Nakamori, Yasushi, Yoshiya, Kazuhisa, Saito, Fukuki, Yoshihara, Tomoyuki, Wada, Daiki, Iwamura, Hiromu, Kanayama, Syuji, Maruyama, Shuhei, Yoshiyama, Takashi, Ohta, Ken, Kokuto, Hiroyuki, Ogata, Hideo, Tanaka, Yoshiaki, Arakawa, Kenichi, Shimoda, Masafumi, Osawa, Takeshi, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Kawada, Miki, Horinouchi, Hirohisa, Saito, Fumitake, Mitamura, Keiko, Hagihara, Masao, Ochi, Junichi, Uchida, Tomoyuki, Baba, Rie, Arai, Daisuke, Ogura, Takayuki, Takahashi, Hidenori, Hagiwara, Shigehiro, Nagao, Genta, Konishi, Shunichiro, Nakachi, Ichiro, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Sano, Hirohito, Matsumoto, Shuichiro, Kimura, Nozomu, Ono, Yoshinao, Baba, Hiroaki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Namba, Shinichi, Suzuki, Ken, Naito, Yoko, Liu, Yu-Chen, Takuwa, Ayako, Sugihara, Fuminori, Wing, James B., Sakakibara, Shuhei, Hizawa, Nobuyuki, Shiroyama, Takayuki, Miyawaki, Satoru, Kawamura, Yusuke, Nakayama, Akiyoshi, Matsuo, Hirotaka, Yuichi, Maeda, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Yamaguchi, Yuta, Murakami, Teruaki, Kuge, Tomoki, Matsumoto, Kinnosuke, Yamamoto, Yuji, Yamamoto, Makoto, Yoneda, Midori, Kishikawa, Toshihiro, Yamada, Shuhei, Kawabata, Shuhei, Kijima, Noriyuki, Takagaki, Masatoshi, Sasa, Noah, Ueno, Yuya, Suzuki, Motoyuki, Takemoto, Norihiko, Eguchi, Hirotaka, Fukusumi, Takahito, Imai, Takao, Fukushima, Munehisa, Kishima, Haruhiko, Inohara, Hidenori, Tomono, Kazunori, Kato, Kazuto, Takahashi, Meiko, Matsuda, Fumihiko, Hirata, Haruhiko, Takeda, Yoshito, Koh, Hidefumi, Manabe, Tadashi, Funatsu, Yohei, Ito, Fumimaro, Fukui, Takahiro, Shinozuka, Keisuke, Kohashi, Sumiko, Miyazaki, Masatoshi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Takaoka, Hatsuyo, Watanabe, Kazuyoshi, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Sugimoto, Hideyasu, Kamiya, Akane, Kuwahara, Naota, Fujiwara, Akiko, Matsunaga, Tomohiro, Sato, Yoko, Okada, Takenori, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Nishi, Koichi, Nishitsuji, Masaru, Tani, Mayuko, Suzuki, Junya, Nakatsumi, Hiroki, Ogura, Takashi, Kitamura, Hideya, Hagiwara, Eri, Murohashi, Kota, Okabayashi, Hiroko, Mochimaru, Takao, Nukaga, Shigenari, Satomi, Ryosuke, Oyamada, Yoshitaka, Mori, Nobuaki, Baba, Tomoya, Fukui, Yasutaka, Odate, Mitsuru, Mashimo, Shuko, Makino, Yasushi, Yagi, Kazuma, Hashiguchi, Mizuha, Kagyo, Junko, Shiomi, Tetsuya, Fuke, Satoshi, Saito, Hiroshi, Tsuchida, Tomoya, Fujitani, Shigeki, Takita, Mumon, Morikawa, Daiki, Yoshida, Toru, Izumo, Takehiro, Inomata, Minoru, Kuse, Naoyuki, Awano, Nobuyasu, Tone, Mari, Ito, Akihiro, Nakamura, Yoshihiko, Hoshino, Kota, Maruyama, Junichi, Ishikura, Hiroyasu, Takata, Tohru, Odani, Toshio, Amishima, Masaru, Hattori, Takeshi, Shichinohe, Yasuo, Kagaya, Takashi, Kita, Toshiyuki, Ohta, Kazuhide, Sakagami, Satoru, Koshida, Kiyoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Kozu, Yutaka, Hiranuma, Hisato, Gon, Yasuhiro, Izumi, Namiki, Nagata, Kaoru, Ueda, Ken, Taki, Reiko, Hanada, Satoko, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Muranaka, Hiroyuki, Nakamura, Kazunori, Hashimoto, Naozumi, Wakahara, Keiko, Koji, Sakamoto, Omote, Norihito, Ando, Akira, Kodama, Nobuhiro, Kaneyama, Yasunari, Shunsuke, Maeda, Kuraki, Takashige, Matsumoto, Takemasa, Yokote, Koutaro, Nakada, Taka-Aki, Abe, Ryuzo, Oshima, Taku, Shimada, Tadanaga, Harada, Masahiro, Takahashi, Takeshi, Ono, Hiroshi, Sakurai, Toshihiro, Shibusawa, Takayuki, Kimizuka, Yoshifumi, Kawana, Akihiko, Sano, Tomoya, Watanabe, Chie, Suematsu, Ryohei, Sageshima, Hisako, Yoshifuji, Ayumi, Ito, Kazuto, Takahashi, Saeko, Ishioka, Kota, Nakamura, Morio, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Ueda, Suguru, Nishikawa, Masanori, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Shinozuka, Jun, Sueyoshi, Atsushi, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Shimo, Masatoshi, Tokunaga, Yoshihisa, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Ogawa, Aki, Inoue, Takuya, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Kan-o, Keiko, Matsumoto, Koichiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Inoue, Yoshiaki, Chiba, Shigeru, Yamagata, Kunihiro, Hiramatsu, Yuji, Kai, Hirayasu, Asano, Koichiro, Oguma, Tsuyoshi, Ito, Yoko, Hashimoto, Satoru, Yamasaki, Masaki, Kasamatsu, Yu, Komase, Yuko, Hida, Naoya, Tsuburai, Takahiro, Oyama, Baku, Takada, Minoru, Kanda, Hidenori, Kitagawa, Yuichiro, Fukuta, Tetsuya, Miyake, Takahito, Yoshida, Shozo, Ogura, Shinji, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Takoi, Hiroyuki, Kikuchi, Ryota, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Wada, Sae, Fujimoto, Nobukazu, Nishiyama, Kei, Terashima, Mariko, Beppu, Satoru, Yoshida, Kosuke, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Umeda, Akira, Miyagawa, Kazuya, Shimada, Hisato, Endo, Mayu, Ohira, Yoshiyuki, Watanabe, Masafumi, Inoue, Sumito, Igarashi, Akira, Sato, Masamichi, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Kimura, Tomoyuki, Shibata, Yoko, Tanino, Yoshinori, Nikaido, Takefumi, Minemura, Hiroyuki, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Takahashi, Hiroshi, Fujii, Kazuhiko, Kishi, Hiroto, Kanai, Masayuki, Imamura, Tomonori, Yamashita, Tatsuya, Yatomi, Masakiyo, Maeno, Toshitaka, Hayashi, Shinichi, Takahashi, Mai, Kuramochi, Mizuki, Kamimaki, Isamu, Tominaga, Yoshiteru, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Tanaka, Toru, Kashiwada, Takeru, Fujita, Kazue, Saito, Yoshinobu, Seike, Masahiro, Watanabe, Hiroko, Matsuse, Hiroto, Kodaka, Norio, Nakano, Chihiro, Oshio, Takeshi, Hirouchi, Takatomo, Makino, Shohei, Egi, Moritoki, Omae, Yosuke, Nannya, Yasuhito, Ueno, Takafumi, Katayama, Kazuhiko, Ai, Masumi, Fukui, Yoshinori, Kumanogoh, Atsushi, Sato, Toshiro, Hasegawa, Naoki, Tokunaga, Katsushi, Ishii, Makoto, Koike, Ryuji, Kitagawa, Yuko, Kimura, Akinori, Imoto, Seiya, Miyano, Satoru, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, Takeshima, Yusuke, Tanaka, Kentaro, Koichi Matsuda, Yamanashi, Yuji, Furukawa, Yoichi, Morisaki, Takayuki, Murakami, Yoshinori, Kamatani, Yoichiro, Muto, Kaori, Nagai, Akiko, Nakamura, Yusuke, Obara, Wataru, Yamaji, Ken, Asai, Satoshi, Takahashi, Yasuo, Higashiue, Shinichi, Kobayashi, Shuzo, Yamaguchi, Hiroki, Nagata, Yasunobu, Wakita, Satoshi, Nito, Chikako, Iwasaki, Yu-ki, Murayama, Shigeo, Yoshimori, Kozo, Miki, Yoshio, Obata, Daisuke, Higashiyama, Masahiko, Masumoto, Akihide, Koga, Yoshinobu, Koretsune, Yukihiro, Yata, Tomohiro, Ogawa, Kotaro, Namkoong, Ho, Okuno, Tatsusada, Liu, Boxiang, Matsuda, Koichi, and Mochizuki, Hideki

Published
2024
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8. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Author

Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu-Jie, Zanoni, Francesca, Liu, Lili, Mladkova, Nikol, Khan, Atlas, Marasa, Maddalena, Zhang, Jun Y., Balderes, Olivia, Sanna-Cherchi, Simone, Bomback, Andrew S., Canetta, Pietro A., Appel, Gerald B., Radhakrishnan, Jai, Trimarchi, Hernan, Sprangers, Ben, Cattran, Daniel C., Reich, Heather, Pei, York, Ravani, Pietro, Galesic, Kresimir, Maixnerova, Dita, Tesar, Vladimir, Stengel, Benedicte, Metzger, Marie, Canaud, Guillaume, Maillard, Nicolas, Berthoux, Francois, Berthelot, Laureline, Pillebout, Evangeline, Monteiro, Renato, Nelson, Raoul, Wyatt, Robert J., Smoyer, William, Mahan, John, Samhar, Al-Akash, Hidalgo, Guillermo, Quiroga, Alejandro, Weng, Patricia, Sreedharan, Raji, Selewski, David, Davis, Keefe, Kallash, Mahmoud, Vasylyeva, Tetyana L., Rheault, Michelle, Chishti, Aftab, Ranch, Daniel, Wenderfer, Scott E., Samsonov, Dmitry, Claes, Donna J., Akchurin, Oleh, Goumenos, Dimitrios, Stangou, Maria, Nagy, Judit, Kovacs, Tibor, Fiaccadori, Enrico, Amoroso, Antonio, Barlassina, Cristina, Cusi, Daniele, Del Vecchio, Lucia, Battaglia, Giovanni Giorgio, Bodria, Monica, Boer, Emanuela, Bono, Luisa, Boscutti, Giuliano, Caridi, Gianluca, Lugani, Francesca, Ghiggeri, GianMarco, Coppo, Rosanna, Peruzzi, Licia, Esposito, Vittoria, Esposito, Ciro, Feriozzi, Sandro, Polci, Rosaria, Frasca, Giovanni, Galliani, Marco, Garozzo, Maurizio, Mitrotti, Adele, Gesualdo, Loreto, Granata, Simona, Zaza, Gianluigi, Londrino, Francesco, Magistroni, Riccardo, Pisani, Isabella, Magnano, Andrea, Marcantoni, Carmelita, Messa, Piergiorgio, Mignani, Renzo, Pani, Antonello, Ponticelli, Claudio, Roccatello, Dario, Salvadori, Maurizio, Salvi, Erica, Santoro, Domenico, Gembillo, Guido, Savoldi, Silvana, Spotti, Donatella, Zamboli, Pasquale, Izzi, Claudia, Alberici, Federico, Delbarba, Elisa, Florczak, Michał, Krata, Natalia, Mucha, Krzysztof, Pączek, Leszek, Niemczyk, Stanisław, Moszczuk, Barbara, Pańczyk-Tomaszewska, Malgorzata, Mizerska-Wasiak, Malgorzata, Perkowska-Ptasińska, Agnieszka, Bączkowska, Teresa, Durlik, Magdalena, Pawlaczyk, Krzysztof, Sikora, Przemyslaw, Zaniew, Marcin, Kaminska, Dorota, Krajewska, Magdalena, Kuzmiuk-Glembin, Izabella, Heleniak, Zbigniew, Bullo-Piontecka, Barbara, Liberek, Tomasz, Dębska-Slizien, Alicja, Hryszko, Tomasz, Materna-Kiryluk, Anna, Miklaszewska, Monika, Szczepańska, Maria, Dyga, Katarzyna, Machura, Edyta, Siniewicz-Luzeńczyk, Katarzyna, Pawlak-Bratkowska, Monika, Tkaczyk, Marcin, Runowski, Dariusz, Kwella, Norbert, Drożdż, Dorota, Habura, Ireneusz, Kronenberg, Florian, Prikhodina, Larisa, van Heel, David, Fontaine, Bertrand, Cotsapas, Chris, Wijmenga, Cisca, Franke, Andre, Annese, Vito, Gregersen, Peter K., Parameswaran, Sreeja, Weirauch, Matthew, Kottyan, Leah, Harley, John B., Suzuki, Hitoshi, Narita, Ichiei, Goto, Shin, Lee, Hajeong, Kim, Dong Ki, Kim, Yon Su, Park, Jin-Ho, Cho, BeLong, Choi, Murim, Van Wijk, Ans, Huerta, Ana, Ars, Elisabet, Ballarin, Jose, Lundberg, Sigrid, Vogt, Bruno, Mani, Laila-Yasmin, Caliskan, Yasar, Barratt, Jonathan, Abeygunaratne, Thilini, Kalra, Philip A., Gale, Daniel P., Panzer, Ulf, Rauen, Thomas, Floege, Jürgen, Schlosser, Pascal, Ekici, Arif B., Eckardt, Kai-Uwe, Chen, Nan, Xie, Jingyuan, Lifton, Richard P., Loos, Ruth J. F., Kenny, Eimear E., Ionita-Laza, Iuliana, Köttgen, Anna, Julian, Bruce A., Novak, Jan, Scolari, Francesco, Zhang, Hong, and Gharavi, Ali G.

Published
2023
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11. A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population

Author

Lee, Jeongeun, Lee, Jean, Jeon, Sungwon, Lee, Jeongha, Jang, Insu, Yang, Jin Ok, Park, Soojin, Lee, Byungwook, Choi, Jinwook, Choi, Byung-Ok, Gee, Heon Yung, Oh, Jaeseong, Jang, In-Jin, Lee, Sanghyuk, Baek, Daehyun, Koh, Youngil, Yoon, Sung-Soo, Kim, Young-Joon, Chae, Jong-Hee, Park, Woong-Yang, Bhak, Jong Hwa, and Choi, Murim

Published
2022
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12. Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis

Author

Shashi, Vandana, Geist, Janelle, Lee, Youngha, Yoo, Yongjin, Shin, Unbeom, Schoch, Kelly, Sullivan, Jennifer, Stong, Nicholas, Smith, Edward, Jasien, Joan, Kranz, Peter, Lee, Yoonsung, Shin, Yong Beom, Wright, Nathan T, Choi, Murim, Kontrogianni‐Konstantopoulos, Aikaterini, Acosta, Maria T, Adams, David R, Aday, Aaron, Alejandro, Mercedes E, Allard, Patrick, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Barbouth, Deborah, Batzli, Gabriel F, Beggs, Alan H, Bellen, Hugo J, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bick, David P, Birch, Camille L, Bivona, Stephanie, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Briere, Lauren C, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chao, Hsiao‐Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Cole, F Sessions, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D'Souza, Precilla, Dasari, Surendra, Davids, Mariska, Davidson, Jean M, Dayal, Jyoti G, Dell'Angelica, Esteban C, Dhar, Shweta U, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Dries, Annika M, Duncan, Laura, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Enns, Gregory M, Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L, Fisher, Paul G, Fogel, Brent L, Forghani, Irman, Friedman, Noah D, Gahl, William A, Godfrey, Rena A, Goldman, Alica M, Goldstein, David B, Gourdine, Jean‐Philippe F, Grajewski, Alana, Groden, Catherine A, Gropman, Andrea L, Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A, High, Frances, and Holm, Ingrid A

Subjects
Biological Sciences, Medical Physiology, Biomedical and Clinical Sciences, Clinical Research, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Adult, Arthrogryposis, Carrier Proteins, Child, Fathers, Female, Humans, Infant, Male, Models, Molecular, Mutation, Neuromuscular Diseases, Pedigree, Phenotype, Protein Conformation, Whole Genome Sequencing, arthrogryposis, hypotonia, MYBPC1, myopathy, myosin binding protein-C, tremor, Undiagnosed Diseases Network, Genetics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

Published
2019

13. Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome

Author

Lee, Sangmoon, Shin, Chang Hoon, Lee, Jawon, Jeong, Seong Dong, Hong, Che Ry, Kim, Jun-Dae, Kim, Ah-Ra, Park, Boryeong, Son, Soo Jin, Kokhan, Oleksandr, Yoo, Taekyeong, Ko, Jae Sung, Sohn, Young Bae, Kim, Ok-Hwa, Ko, Jung Min, Cho, Tae-Joon, Wright, Nathan T., Seong, Je Kyung, Jin, Suk-Won, Kang, Hyoung Jin, Kim, Hyeon Ho, and Choi, Murim

Published
2021
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14. Defining the phenotypic spectrum of SLC6A1 mutations

Author

Johannesen, Katrine M, Gardella, Elena, Linnankivi, Tarja, Courage, Carolina, Martin, Anne Saint, Lehesjoki, Anna‐Elina, Mignot, Cyril, Afenjar, Alexandra, Lesca, Gaetan, Abi‐Warde, Marie‐Thérèse, Chelly, Jamel, Piton, Amélie, Merritt, J Lawrence, Rodan, Lance H, Tan, Wen‐Hann, Bird, Lynne M, Nespeca, Mark, Gleeson, Joseph G, Yoo, Yongjin, Choi, Murim, Chae, Jong‐Hee, Czapansky‐Beilman, Desiree, Reichert, Sara Chadwick, Pendziwiat, Manuela, Verhoeven, Judith S, Schelhaas, Helenius J, Devinsky, Orrin, Christensen, Jakob, Specchio, Nicola, Trivisano, Marina, Weber, Yvonne G, Nava, Caroline, Keren, Boris, Doummar, Diane, Schaefer, Elise, Hopkins, Sarah, Dubbs, Holly, Shaw, Jessica E, Pisani, Laura, Myers, Candace T, Tang, Sha, Tang, Shan, Pal, Deb K, Millichap, John J, Carvill, Gemma L, Helbig, Kathrine L, Mecarelli, Oriano, Striano, Pasquale, Helbig, Ingo, Rubboli, Guido, Mefford, Heather C, and Møller, Rikke S

Subjects
Behavioral and Social Science, Neurodegenerative, Neurosciences, Genetics, Epilepsy, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Anticonvulsants, Ataxia, Child, Child, Preschool, Cohort Studies, Electroencephalography, Epilepsies, Myoclonic, Epilepsies, Partial, Epilepsy, Generalized, Female, GABA Plasma Membrane Transport Proteins, Genetic Association Studies, Humans, Intellectual Disability, Language Development Disorders, Male, Mutation, Mutation, Missense, Neurodevelopmental Disorders, Phenotype, Treatment Outcome, Valproic Acid, Young Adult, epilepsy, epilepsy genetics, MAE, SLC6A1, MAE, SLC6A1, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectivePathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.MethodsWe collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.ResultsCognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).SignificanceMost patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

Published
2018

15. The Korean undiagnosed diseases program phase I: expansion of the nationwide network and the development of long-term infrastructure

Author

Kim, Soo Yeon, Lee, Seungbok, Woo, Hyewon, Han, Jiyeon, Ko, Young Jun, Shim, Youngkyu, Park, Soojin, Jang, Se Song, Lim, Byung Chan, Ko, Jung Min, Kim, Ki Joong, Cho, Anna, Kim, Hunmin, Hwang, Hee, Choi, Ji Eun, Kim, Man Jin, Moon, Jangsup, Seong, Moon-Woo, Park, Sung Sup, Choi, Sun Ah, Lee, Ji Eun, Kwon, Young Se, Sohn, Young Bae, Kim, Jon Soo, Kim, Won Seop, Lee, Yun Jeong, Kwon, Soonhak, Kim, Young Ok, Kook, Hoon, Cho, Yong Gon, Cheon, Chong Kun, Kang, Ki-Soo, Song, Mi-Ryoung, Kim, Young-Joon, Cha, Hyuk-Jin, Choi, Hee-Jung, Kee, Yun, Park, Sung-Gyoo, Baek, Seung Tae, Choi, Murim, Ryu, Dong-Sung, and Chae, Jong-Hee

Published
2022
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18. Polygenic Landscape of Cryptogenic New‐Onset Refractory Status Epilepticus: A Comprehensive Whole‐Genome Sequencing Study.

Author

Jang, Yoonhyuk, Hong, Sung Eun, Ahn, Soo Hyun, Mon, Su Yee, You, Ji Hye, Chu, Kon, Lee, Sang Kun, Choi, Murim, and Lee, Soon‐Tae

Subjects
STATUS epilepticus, CENTRAL nervous system, AUTOINFLAMMATORY diseases, PHENOTYPES, ENCEPHALITIS
Abstract

Cryptogenic new‐onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole‐genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024;96:1201–1208 [ABSTRACT FROM AUTHOR]

Published
2024
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19. Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

Author

Chung, Hyung-lok, Wangler, Michael F., Marcogliese, Paul C., Jo, Juyeon, Ravenscroft, Thomas A., Zuo, Zhongyuan, Duraine, Lita, Sadeghzadeh, Sina, Li-Kroeger, David, Schmidt, Robert E., Pestronk, Alan, Rosenfeld, Jill A., Burrage, Lindsay, Herndon, Mitchell J., Chen, Shan, Shillington, Amelle, Vawter-Lee, Marissa, Hopkin, Robert, Rodriguez-Smith, Jackeline, Henrickson, Michael, Lee, Brendan, Moser, Ann B., Jones, Richard O., Watkins, Paul, Yoo, Taekyeong, Mar, Soe, Choi, Murim, Bucelli, Robert C., Yamamoto, Shinya, Lee, Hyun Kyoung, Prada, Carlos E., Chae, Jong-Hee, Vogel, Tiphanie P., and Bellen, Hugo J.

Published
2020
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23. Melatonin alleviates myocardial dysfunction through inhibition of endothelial‐to‐mesenchymal transition via the NF‐κB pathway

Author

Kim, Ran, primary, Kim, Minsuk, additional, Jeong, Seongtae, additional, Kim, Sejin, additional, Moon, Hanbyeol, additional, Kim, Hojin, additional, Lee, Min Young, additional, Kim, Jongmin, additional, Kim, Hyung‐Sik, additional, Choi, Murim, additional, Shin, Kunyoo, additional, Song, Byeong‐Wook, additional, and Chang, Woochul, additional

Published
2024
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26. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Author

Cromer, M, Choi, Murim, Nelson-Williams, Carol, Fonseca, Annabelle, Kunstman, John, Korah, Reju, Overton, John, Mane, Shrikant, Kenney, Barton, Malchoff, Carl, Stalberg, Peter, Akerström, Göran, Westin, Gunnar, Hellman, Per, Carling, Tobias, Björklund, Peyman, and Lifton, Richard

Subjects
YY1, adenylyl cyclase, cAMP, exome sequencing, insulinoma, Adenylyl Cyclases, Adolescent, Adult, Aged, Aged, 80 and over, Base Sequence, Binding Sites, Blood Glucose, Calcium, Calcium Channels, Cohort Studies, Cyclic AMP, Female, Gene Expression Regulation, Humans, Insulin, Insulin-Secreting Cells, Insulinoma, Male, Middle Aged, Molecular Sequence Data, Mutation, Missense, Pancreatic Neoplasms, Protein Binding, YY1 Transcription Factor
Abstract

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Published
2015

27. Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds

Author

Yang, Jie, Wang, Shih-Kai, Choi, Murim, Reid, Bryan M, Hu, Yuanyuan, Lee, Yuan-Ling, Herzog, Curtis R, Kim-Berman, Hera, Lee, Moses, Benke, Paul J, Lloyd, KC Kent, Simmer, James P, and Hu, Jan C-C

Subjects
Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Genetics, Pediatric, Congenital Structural Anomalies, Dental/Oral and Craniofacial Disease, Familial tooth agenesis, hypodontia, oligodontia, taurodontism, oligodontia, taurodontism, Clinical Sciences, Medicinal and biomolecular chemistry
Abstract

WNT10A is a signaling molecule involved in tooth development, and WNT10A defects are associated with tooth agenesis. We characterized Wnt10a null mice generated by the knockout mouse project (KOMP) and six families with WNT10A mutations, including a novel p.Arg104Cys defect, in the absence of EDA,EDAR, or EDARADD variations. Wnt10a null mice exhibited supernumerary mandibular fourth molars, and smaller molars with abnormal cusp patterning and root taurodontism. Wnt10a (-/-) incisors showed distinctive apical-lingual wedge-shaped defects. These findings spurred us to closely examine the dental phenotypes of our WNT10A families. WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. Individuals with two defective WNT10A alleles showed severe tooth agenesis and had fewer cusps on their molars. The misshapened molar crowns and roots were consistent with the Wnt10a null phenotype and were not previously associated with WNT10A defects. The missing teeth contrasted with the presence of supplemental teeth in the Wnt10a null mice and demonstrated mammalian species differences in the roles of Wnt signaling in early tooth development. We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles.

Published
2015

31. Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Author

Kour, Sukhleen, Rajan, Deepa S., Fortuna, Tyler R., Anderson, Eric N., Ward, Caroline, Lee, Youngha, Lee, Sangmoon, Shin, Yong Beom, Chae, Jong-Hee, Choi, Murim, Siquier, Karine, Cantagrel, Vincent, Amiel, Jeanne, Stolerman, Elliot S., Barnett, Sarah S., Cousin, Margot A., Castro, Diana, McDonald, Kimberly, Kirmse, Brian, Nemeth, Andrea H., Rajasundaram, Dhivyaa, Innes, A. Micheil, Lynch, Danielle, Frosk, Patrick, Collins, Abigail, Gibbons, Melissa, Yang, Michele, Desguerre, Isabelle, Boddaert, Nathalie, Gitiaux, Cyril, Rydning, Siri Lynne, Selmer, Kaja K., Urreizti, Roser, Garcia-Oguiza, Alberto, Osorio, Andrés Nascimento, Verdura, Edgard, Pujol, Aurora, McCurry, Hannah R., Landers, John E., Agnihotri, Sameer, Andriescu, E. Corina, Moody, Shade B., Phornphutkul, Chanika, Sacoto, Maria J. Guillen, Begtrup, Amber, Houlden, Henry, Kirschner, Janbernd, Schorling, David, Rudnik-Schöneborn, Sabine, Strom, Tim M., Leiz, Steffen, Juliette, Kali, Richardson, Randal, Yang, Ying, Zhang, Yuehua, Wang, Minghui, Wang, Jia, Wang, Xiaodong, Platzer, Konrad, Donkervoort, Sandra, Bönnemann, Carsten G., Wagner, Matias, Issa, Mahmoud Y., Elbendary, Hasnaa M., Stanley, Valentina, Maroofian, Reza, Gleeson, Joseph G., Zaki, Maha S., Senderek, Jan, and Pandey, Udai Bhan

Published
2021
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35. Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Author

Chang, Hae Ryung, Cho, Sung Yoon, Lee, Jae Hoon, Lee, Eunkyung, Seo, Jieun, Lee, Hye Ran, Cavalcanti, Denise P., Mäkitie, Outi, Valta, Helena, Girisha, Katta M., Lee, Chung, Neethukrishna, Kausthubham, Bhavani, Gandham S., Shukla, Anju, Nampoothiri, Sheela, Phadke, Shubha R., Park, Mi Jung, Ikegawa, Shiro, Wang, Zheng, Higgs, Martin R., Stewart, Grant S., Jung, Eunyoung, Lee, Myeong-Sok, Park, Jong Hoon, Lee, Eun A., Kim, Hongtae, Myung, Kyungjae, Jeon, Woosung, Lee, Kyoungyeul, Kim, Dongsup, Kim, Ok-Hwa, Choi, Murim, Lee, Han-Woong, Kim, Yonghwan, and Cho, Tae-Joon

Published
2019
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36. Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Author

Park, Jong‐Chan, Han, Jong Won, Lee, Woochan, Kim, Jieun, Lee, Sang‐Eun, Lee, Dongjoon, Choi, Hayoung, Han, Jihui, Kang, You Jung, Diep, Yen N., Cho, Hansang, Kang, Rian, Yu, Won Jong, Lee, Jean, Choi, Murim, Im, Sun‐Wha, Kim, Jong‐Il, and Mook‐Jung, Inhee

Subjects
MYELOID cells, ALZHEIMER'S disease, FRAMESHIFT mutation, AMYLOID plaque, PHOSPHATIDYLSERINES
Abstract

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta‐amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2‐mediated phagocytosis of beta‐amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co‐culture systems with loss‐of‐function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR‐Cas9‐based APOE4 lines) and familial (APPNL‐G‐F/MAPT double knock‐in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer‐positive Aβ plaques. Herein new insight is provided into TREM2‐dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression. [ABSTRACT FROM AUTHOR]

Published
2024
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37. Moderation of thyroid hormones for the relationship between amyloid and tau pathology.

Author

Byeon, Jeong Hyeon, Byun, Min Soo, Yi, Dahyun, Jung, Joon Hyung, Sohn, Bo Kyung, Chang, Yoon Young, Kong, Nayeong, Jung, Gijung, Ahn, Hyejin, Lee, Jun-Young, Lee, Yun-Sang, Kim, Yu Kyeong, Lee, Dong Young, Sohn, Chul-Ho, Jung, Inhee Mook-, Choi, Murim, Lee, Yu Jin, Hahn, Seokyung, Kim, Hyun Jung, and Chang, Mun Young

Subjects
THYROID hormones, DISEASE risk factors, TAU proteins, POSITRON emission tomography, AMYLOID
Abstract

Background: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition. Methods: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. Results: No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition. Conclusion: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Author

Gupta, Abha, Pirruccello, Michelle, Cheng, Feng, Kang, Hyo, Fernandez, Thomas, Baskin, Jeremy, Choi, Murim, Liu, Li, Ercan-Sencicek, Adife, Murdoch, John, Klei, Lambertus, Neale, Benjamin, Franjic, Daniel, Daly, Mark, Lifton, Richard, De Camilli, Pietro, Zhao, Hongyu, Sestan, Nenad, and State, Matthew

Subjects
Autism spectrum disorder, EFR3A, Genetics, Phosphoinositide metabolism, Rare variants, Synapse
Abstract

BACKGROUND: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. METHODS: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. RESULTS: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P

Published
2014

39. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

Author

Ashraf, Shazia, Gee, Heon Yung, Woerner, Stephanie, Xie, Letian X, Vega-Warner, Virginia, Lovric, Svjetlana, Fang, Humphrey, Song, Xuewen, Cattran, Daniel C, Avila-Casado, Carmen, Paterson, Andrew D, Nitschké, Patrick, Bole-Feysot, Christine, Cochat, Pierre, Esteve-Rudd, Julian, Haberberger, Birgit, Allen, Susan J, Zhou, Weibin, Airik, Rannar, Otto, Edgar A, Barua, Moumita, Al-Hamed, Mohamed H, Kari, Jameela A, Evans, Jonathan, Bierzynska, Agnieszka, Saleem, Moin A, Böckenhauer, Detlef, Kleta, Robert, Desoky, Sherif El, Hacihamdioglu, Duygu O, Gok, Faysal, Washburn, Joseph, Wiggins, Roger C, Choi, Murim, Lifton, Richard P, Levy, Shawn, Han, Zhe, Salviati, Leonardo, Prokisch, Holger, Williams, David S, Pollak, Martin, Clarke, Catherine F, Pei, York, Antignac, Corinne, and Hildebrandt, Friedhelm

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Complementary and Integrative Health, Aetiology, 2.1 Biological and endogenous factors, Renal and urogenital, Adolescent, Adrenal Cortex Hormones, Amino Acid Sequence, Animals, Cells, Cultured, Child, Consanguinity, Conserved Sequence, DNA Mutational Analysis, Disease Models, Animal, Drosophila Proteins, Drug Resistance, Exome, Fibroblasts, Gene Knockdown Techniques, Humans, Mitochondria, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Podocytes, Protein Kinases, Rats, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquinone, Young Adult, Zebrafish, Zebrafish Proteins, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

Published
2013

40. Mutations in DSTYK and Dominant Urinary Tract Malformations

Author

Sanna-Cherchi, Simone, Sampogna, Rosemary V, Papeta, Natalia, Burgess, Katelyn E, Nees, Shannon N, Perry, Brittany J, Choi, Murim, Bodria, Monica, Liu, Yan, Weng, Patricia L, Lozanovski, Vladimir J, Verbitsky, Miguel, Lugani, Francesca, Sterken, Roel, Paragas, Neal, Caridi, Gianluca, Carrea, Alba, Dagnino, Monica, Materna-Kiryluk, Anna, Santamaria, Giuseppe, Murtas, Corrado, Ristoska-Bojkovska, Nadica, Izzi, Claudia, Kacak, Nilgun, Bianco, Beatrice, Giberti, Stefania, Gigante, Maddalena, Piaggio, Giorgio, Gesualdo, Loreto, Vukic, Durdica Kosuljandic, Vukojevic, Katarina, Saraga-Babic, Mirna, Saraga, Marijan, Gucev, Zoran, Allegri, Landino, Latos-Bielenska, Anna, Casu, Domenica, State, Matthew, Scolari, Francesco, Ravazzolo, Roberto, Kiryluk, Krzysztof, Al-Awqati, Qais, D'Agati, Vivette D, Drummond, Iain A, Tasic, Velibor, Lifton, Richard P, Ghiggeri, Gian Marco, and Gharavi, Ali G

Subjects
Urologic Diseases, Pediatric, Congenital Structural Anomalies, Human Genome, Kidney Disease, Biotechnology, Genetics, Clinical Research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Renal and urogenital, Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinases, Urinary Tract, Urogenital Abnormalities, Young Adult, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

Published
2013

41. De novo mutations in histone-modifying genes in congenital heart disease.

Author

Zaidi, Samir, Choi, Murim, Wakimoto, Hiroko, Ma, Lijiang, Jiang, Jianming, Overton, John, Romano-Adesman, Angela, Bjornson, Robert, Breitbart, Roger, Brown, Kerry, Carriero, Nicholas, Cheung, Yee, Deanfield, John, DePalma, Steve, Fakhro, Khalid, Glessner, Joseph, Hakonarson, Hakon, Italia, Michael, Kaltman, Jonathan, Kaski, Juan, Kim, Richard, Kline, Jennie, Lee, Teresa, Leipzig, Jeremy, Lopez, Alexander, Mane, Shrikant, Mitchell, Laura, Newburger, Jane, Parfenov, Michael, Peer, Itsik, Porter, George, Roberts, Amy, Sachidanandam, Ravi, Subramanian, Sailakshmi, Tikhonova, Irina, Wang, Wei, Warburton, Dorothy, White, Peter, Williams, Ismee, Zhao, Hongyu, Seidman, Jonathan, Brueckner, Martina, Chung, Wendy, Gelb, Bruce, Goldmuntz, Elizabeth, Seidman, Christine, Lifton, Richard, Seiden, Howard, State, Matthew, and Sanders, Stephan

Subjects
Adult, Case-Control Studies, Child, Chromatin, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Female, Genes, Developmental, Heart Diseases, Histones, Humans, Lysine, Male, Methylation, Mutation, Odds Ratio, Promoter Regions, Genetic
Abstract

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes poised promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Published
2013

42. Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Author

Clark, Victoria E, Erson-Omay, E Zeynep, Serin, Akdes, Yin, Jun, Cotney, Justin, Özduman, Koray, Avşar, Timuçin, Li, Jie, Murray, Phillip B, Henegariu, Octavian, Yilmaz, Saliha, Günel, Jennifer Moliterno, Carrión-Grant, Geneive, Yılmaz, Baran, Grady, Conor, Tanrıkulu, Bahattin, Bakırcıoğlu, Mehmet, Kaymakçalan, Hande, Caglayan, Ahmet Okay, Sencar, Leman, Ceyhun, Emre, Atik, A Fatih, Bayri, Yaşar, Bai, Hanwen, Kolb, Luis E, Hebert, Ryan M, Omay, S Bulent, Mishra-Gorur, Ketu, Choi, Murim, Overton, John D, Holland, Eric C, Mane, Shrikant, State, Matthew W, Bilgüvar, Kaya, Baehring, Joachim M, Gutin, Philip H, Piepmeier, Joseph M, Vortmeyer, Alexander, Brennan, Cameron W, Pamir, M Necmettin, Kılıç, Türker, Lifton, Richard P, Noonan, James P, Yasuno, Katsuhito, and Günel, Murat

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Rare Diseases, Brain Cancer, Neurosciences, Human Genome, Cancer, Adult, Aged, Aged, 80 and over, Brain Neoplasms, Chromosomes, Human, Pair 22, DNA Mutational Analysis, Female, Genes, Neurofibromatosis 2, Genomic Instability, Genomics, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Male, Meningeal Neoplasms, Meningioma, Middle Aged, Mutation, Neoplasm Grading, Proto-Oncogene Proteins c-akt, Receptors, G-Protein-Coupled, Smoothened Receptor, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, General Science & Technology
Abstract

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Published
2013

43. Identification of Somatic Mutations in Parathyroid Tumors Using Whole-Exome Sequencing

Author

Cromer, M Kyle, Starker, Lee F, Choi, Murim, Udelsman, Robert, Nelson-Williams, Carol, Lifton, Richard P, and Carling, Tobias

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Human Genome, Cancer Genomics, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Adenoma, Cohort Studies, DNA Mutational Analysis, DNA, Neoplasm, Enhancer of Zeste Homolog 2 Protein, Exons, Humans, Multiple Endocrine Neoplasia Type 1, Mutation, Parathyroid Neoplasms, Polycomb Repressive Complex 2, Polymerase Chain Reaction, Reproducibility of Results, Sequence Analysis, DNA, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences
Abstract

ContextThe underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined.ObjectiveThe aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing.DesignEight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas.ResultsFour of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing.ConclusionThis study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.

Published
2012

44. Familial cortical myoclonus with a mutation in NOL3.

Author

Russell, Jonathan, Steckley, Jamie, Hahn, Angelika, Howard, MacKenzie, Kornberg, Zachary, Huang, Alden, Mirsattari, Seyed, Merriman, Barry, Klein, Eric, Choi, Murim, Lee, Hsien-Yang, Kirk, Andrew, Nelson-Williams, Carol, Gibson, Gillian, Ptáček, Louis, Lifton, Richard, Baraban, Scott, Fu, Ying-hui, Coppola, Giovanni, and Geschwind, Daniel

Subjects
Adolescent, Adult, Age of Onset, Animals, Apoptosis Regulatory Proteins, Canada, Cell Line, Transformed, Chromosome Mapping, Chromosomes, Human, Pair 16, Electroencephalography, Family Health, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Male, Mice, Middle Aged, Muscle Proteins, Mutation, Myoclonus, Phenotype, Proline, Transfection
Abstract

OBJECTIVE: Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype. METHODS: A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation. RESULTS: We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro. INTERPRETATION: We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.

Published
2012

45. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

Author

Bilgüvar, Kaya, Oztürk, Ali Kemal, Louvi, Angeliki, Kwan, Kenneth Y, Choi, Murim, Tatli, Burak, Yalnizoğlu, Dilek, Tüysüz, Beyhan, Cağlayan, Ahmet Okay, Gökben, Sarenur, Kaymakçalan, Hande, Barak, Tanyeri, Bakircioğlu, Mehmet, Yasuno, Katsuhito, Ho, Winson, Sanders, Stephan, Zhu, Ying, Yilmaz, Sanem, Dinçer, Alp, Johnson, Michele H, Bronen, Richard A, Koçer, Naci, Per, Hüseyin, Mane, Shrikant, Pamir, Mehmet Necmettin, Yalçinkaya, Cengiz, Kumandaş, Sefer, Topçu, Meral, Ozmen, Meral, Sestan, Nenad, Lifton, Richard P, State, Matthew W, and Günel, Murat

Subjects
Brain, Animals, Humans, Mice, Microcephaly, Brain Diseases, Nerve Tissue Proteins, Pedigree, DNA Mutational Analysis, Base Sequence, Genes, Recessive, Mutation, Molecular Sequence Data, Female, Male, Genes, Recessive, General Science & Technology
Abstract

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Published
2010

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