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201. Isoform Switch of TET1 Regulates DNA Demethylation and Mouse Development

Author

Zhang, Wenhao, Xia, Weikun, Wang, Qiujun, Towers, Aaron J., Chen, Jiayu, Gao, Rui, Zhang, Yu, Yen, Chia-An, Lee, Ah Young, Li, Yuanyuan, Zhou, Chen, Liu, Kaili, Zhang, Jing, Gu, Tian-Peng, Chen, Xiuqi, Chang, Zai, Leung, Danny Chi Yeu, Gao, Shaorong, Jiang, Yong-Hui, Xie, Wei, Zhang, Wenhao, Xia, Weikun, Wang, Qiujun, Towers, Aaron J., Chen, Jiayu, Gao, Rui, Zhang, Yu, Yen, Chia-An, Lee, Ah Young, Li, Yuanyuan, Zhou, Chen, Liu, Kaili, Zhang, Jing, Gu, Tian-Peng, Chen, Xiuqi, Chang, Zai, Leung, Danny Chi Yeu, Gao, Shaorong, Jiang, Yong-Hui, and Xie, Wei

Abstract

The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. However, it remains elusive how exactly they target substrates and execute oxidation. Interestingly, we found that, in mice, the full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (ESCs), and primordial germ cells (PGCs). By contrast, a short isoform (TET1s) is preferentially expressed in somatic cells, which lacks the N terminus including the CXXC domain, a DNA-binding module that often recognizes CpG islands (CGIs) where TET1 predominantly occupies. Unexpectedly, TET1s can still bind CGIs despite the fact that its global chromatin binding is significantly reduced. Interestingly, global chromatin binding, but not targeted binding at CGIs, is correlated with TET1-mediated demethylation. Finally, mice with exclusive expression of Tet1s failed to erase imprints in PGCs and displayed developmental defects in progeny. These data show that isoform switch of TET1 regulates epigenetic memory erasure and mouse development. © 2016 Elsevier Inc.

Published
2016

202. Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy

Author

Acosta, Maria T., Adams, David R., Agrawal, Pankaj, Alejandro, Mercedes E., Allard, Patrick, Alvey, Justin, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Barbouth, Deborah, Batzli, Gabriel F., Bayrak-Toydemir, Pinar, Beggs, Alan H., Bejerano, Gill, Bellen, Hugo J., Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bick, David P., Birch, Camille L., Bivona, Stephanie, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Botto, Lorenzo, Briere, Lauren C., Brokamp, Elly, Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Carey, John, 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, Dayal, Jyoti G., Dell'Angelica, Esteban C., Dhar, Shweta U., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Duncan, Laura, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, 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., Hayes, Nichole, High, Frances, Holm, Ingrid A., Hom, Jason, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Karaviti, Lefkothea, Kelley, Emily G., Kiley, Dana, Koeller, David M., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Kyle, Jennifer E., Lalani, Seema R., Lam, Byron, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Loo, Sandra K., Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Metz, Thomas O., Might, Matthew, Morava-Kozicz, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nath, Avi, Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pallais, J. Carl, Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raja, Archana N., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rowley, Robb K., Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Shakachite, Lisa, Sharma, Prashant, Shashi, Vandana, Shields, Kathleen, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Kevin S., Solnica-Krezel, Lilianna, Spillmann, Rebecca C., Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sutton, Shirley, Sweetser, David A., Tabor, Holly K., Tamburro, Cecelia P., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Wegner, Daniel, Westerfield, Monte, Wheeler, Matthew T., Wise, Anastasia L., Wolfe, Lynne A., Woods, Jeremy D., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, John, Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Bhatia, Aashim, Mobley, Bret C., Cogan, Joy, Koziura, Mary E., Phillips, John, Newman, John, and Moore, Steven A.

Published
2019
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203. De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

Author

Shashi, Vandana, primary, Pena, Loren D.M., additional, Kim, Katherine, additional, Burton, Barbara, additional, Hempel, Maja, additional, Schoch, Kelly, additional, Walkiewicz, Magdalena, additional, McLaughlin, Heather M., additional, Cho, Megan, additional, Stong, Nicholas, additional, Hickey, Scott E., additional, Shuss, Christine M., additional, Freemark, Michael S., additional, Bellet, Jane S., additional, Keels, Martha Ann, additional, Bonner, Melanie J., additional, El-Dairi, Maysantoine, additional, Butler, Megan, additional, Kranz, Peter G., additional, Stumpel, Constance T.R.M., additional, Klinkenberg, Sylvia, additional, Oberndorff, Karin, additional, Alawi, Malik, additional, Santer, Rene, additional, Petrovski, Slavé, additional, Kuismin, Outi, additional, Korpi-Heikkilä, Satu, additional, Pietilainen, Olli, additional, Aarno, Palotie, additional, Kurki, Mitja I., additional, Hoischen, Alexander, additional, Need, Anna C., additional, Goldstein, David B., additional, Kortüm, Fanny, additional, Bacino, A., additional, Lee, Brendan H., additional, Balasubramanyam, Ashok, additional, Burrage, Lindsay C., additional, Clark, Gary D., additional, Craigen, William J., additional, Dhar, Shweta U., additional, Emrick, Lisa T., additional, Graham, Brett H., additional, Jain, Mahim, additional, Lalani, Seema R., additional, Lewis, Richard A., additional, Moretti, Paolo M., additional, Nicholas, Sarah K., additional, Orange, Jordan S., additional, Posey, Jennifer E., additional, Potocki, Lorraine, additional, Rosenfeld, Jill A., additional, Scott, Daryl A., additional, Hanchard, Neil A., additional, Alyssa, Tran A., additional, Mercedes, Alejandro E., additional, Mashid, Azamian S., additional, Bellen, Hugo J., additional, Yamamoto, Shinya, additional, Wangler, Michael F., additional, Westerfield, Monte, additional, Postlethwait, John H., additional, Eng, Christine M., additional, Yang, Yaping, additional, Muzny, Donna M., additional, Ward, Patricia A., additional, Ramoni, Rachel B., additional, McCray, Alexa T., additional, Kohane, Issac S., additional, Holm, Ingrid A., additional, Might, Matthew, additional, Mazur, Paul, additional, Splinter, Kimberly, additional, Esteves, Cecilia, additional, Shashi, Vandana, additional, Jiang, Yong-hui, additional, McConkie-Rosell, Allyn, additional, Spillmann, Rebecca C., additional, Sullivan, Jennifer A., additional, Walley, Nicole M., additional, Beggs, Alan H., additional, Loscalzo, Joseph, additional, MacRae, Calum A., additional, Silverman, Edwin K., additional, Stoler, Joan M., additional, Sweetser, David A., additional, Maas, Richard L., additional, Krier, Joel B., additional, Rodan, Lance H., additional, Walsh, Chris A., additional, Cooper, Cynthia M., additional, Pallais, Juan C., additional, Donnell-Fink, Laurel A., additional, Krieg, Elizabeth L., additional, Lincoln, Sharyn A., additional, Briere, Lauren C., additional, Jacob, Howard J., additional, Worthey, Elizabeth A., additional, Lazar, Joe, additional, Strong, Kim A., additional, Handley, Lori H., additional, Newberry, J. Scott, additional, Bick, David P., additional, Schroeder, Molly C., additional, Brown, Donna M., additional, Birch, Camille L., additional, Levy, Shawn E., additional, Boone, Braden E., additional, Dorset, Dan C., additional, Jones, Angela L., additional, Manolio, Teri A., additional, Mulvihill, John J., additional, Wise, Anastasia L., additional, Dayal, Jyoti G., additional, Eckstein, David J., additional, Krasnewich, Donna M., additional, Loomis, Carson R., additional, Mamounas, Laura A., additional, Iglesias, Brenda, additional, Martin, Casey, additional, Koeller, David M., additional, Metz, Thomas O., additional, Ashley, Euan A., additional, Fisher, Paul G., additional, Bernstein, Jonathan A., additional, Wheeler, Matt T., additional, Zornio, Patricia A., additional, Waggott, Daryl M., additional, Dries, Annika M., additional, Kohler, Jennefer N., additional, Dipple, Katrina M., additional, Nelson, Stan F., additional, Palmer, Christina G.S., additional, Vilain, Eric, additional, Allard, Patrick, additional, Dell Angelica, Esteban C., additional, Lee, Hane, additional, Sinsheimer, Janet S., additional, Papp, Jeanette C., additional, Dorrani, Naghmeh, additional, Herzog, Matthew R., additional, Barseghyan, Hayk, additional, Adams, David R., additional, Adams, Christopher J., additional, Burke, Elizabeth A., additional, Chao, Katherine R., additional, Davids, Mariska, additional, Draper, David D., additional, Estwick, Tyra, additional, Frisby, Trevor S., additional, Frost, Kate, additional, Gahl, William A., additional, Gartner, Valerie, additional, Godfrey, Rena A., additional, Goheen, Mitchell, additional, Golas, Gretchen A., additional, Gordon, Mary G., additional, Groden, Catherine A., additional, Gropman, Andrea L., additional, Hackbarth, Mary E., additional, Hardee, Isabel, additional, Johnston, Jean M., additional, Koehler, Alanna E., additional, Latham, Lea, additional, Latour, Yvonne L., additional, Lau, Chyau Yueh C., additional, Lee, Paul R., additional, Levy, Denise J., additional, Liebendorder, Adam P., additional, Macnamara, Ellen F., additional, Maduro, Valerie V., additional, Malicdan, May V., additional, Markello, Thomas C., additional, McCarty, Alexandra J., additional, Murphy, Jennifer L., additional, Nehrebecky, Michele E., additional, Novacic, Donna, additional, Pusey, Barbara N., additional, Sadozai, Sarah, additional, Schaffer, Katherine E., additional, Sharma, Prashant, additional, Soldatos, Ariane G., additional, Thomas, Sara P., additional, Tifft, Cynthia J., additional, Tolman, Nathanial J., additional, Toro, Camilo, additional, Valivullah, Zaheer M., additional, Wahl, Colleen E., additional, Warburton, Mike, additional, Weech, Alec A., additional, Wolfe, Lynne A., additional, Yu, Guoyun, additional, Hamid, Rizwan, additional, Newman, John H., additional, Phillips, John A., additional, and Cogan, Joy D., additional

Published
2016
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204. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

Author

Bentler, Kristi, primary, Zhai, Shaohui, additional, Elsbecker, Sara A., additional, Arnold, Georgianne L., additional, Burton, Barbara K., additional, Vockley, Jerry, additional, Cameron, Cynthia A., additional, Hiner, Sally J., additional, Edick, Mathew J., additional, Berry, Susan A., additional, Thomas, Janet, additional, Dodge, Melinda, additional, Singh, Rani, additional, Lakshman, Sangeetha, additional, Coakley, Katie, additional, Stembridge, Adrya, additional, Russi, Alvaro Serrano, additional, Phillips, Emily, additional, Burton, Barbara, additional, Edano, Clare, additional, Shrestha, Sheela, additional, Hoganson, George, additional, Dwyer, Lauren, additional, Hainline, Bryan, additional, Romie, Susan, additional, Hainline, Sarah, additional, Asamoah, Alexander, additional, Goodin, Kara, additional, Rajakaruna, Cecilia, additional, Jackson, Kelly, additional, Hamosh, Ada, additional, Vernon, Hilary, additional, Smith, Nancy, additional, Ahmad, Ayesha, additional, Lipinski, Sue, additional, Feldman, Gerald, additional, Berry, Susan, additional, Elsbecker, Sara, additional, Bentler, Kristi, additional, Font-Montgomery, Esperanza, additional, Peck, Dawn, additional, Pena, Loren D.M., additional, Koeberl, Dwight D., additional, Jiang, Yong-hui, additional, Kishnani, Priya S., additional, Rizzo, William, additional, Dawson, Machelle, additional, Ambrose, Nancy, additional, Levy, Paul, additional, Kronn, David, additional, Fong, Chin-to, additional, D’Aco, Kristin, additional, Hart, Theresa, additional, Erbe, Richard, additional, Samons, Melissa, additional, Leslie, Nancy, additional, Powers, Racheal, additional, Bartholomew, Dennis, additional, Goff, Melanie, additional, vanCalcar, Sandy, additional, Hansen, Joyanna, additional, Arnold, Georgianne, additional, Walsh-Vockley, Cate, additional, Rhead, William, additional, Dimmock, David, additional, Engelking, Paula, additional, Bird, Cassie, additional, Swan, Ashley, additional, Schwoerer, Jessica Scott, additional, Henry, Sonja, additional, Narumanchi, TaraChandra, additional, Hummel, Marybeth, additional, Wilkins, Jennie, additional, Davis-Keppen, Laura, additional, Stein, Quinn, additional, Loman, Rebecca, additional, Cameron, Cynthia, additional, and Justice, Kaitlin, additional

Published
2016
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205. The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

Author

Mansour, Mariam, primary, Haupt, Sue, additional, Chan, Ai-Leen, additional, Godde, Nathan, additional, Rizzitelli, Alexandra, additional, Loi, Sherene, additional, Caramia, Franco, additional, Deb, Siddhartha, additional, Takano, Elena A., additional, Bishton, Mark, additional, Johnstone, Cameron, additional, Monahan, Brendon, additional, Levav-Cohen, Yarra, additional, Jiang, Yong-Hui, additional, Yap, Alpha S., additional, Fox, Stephen, additional, Bernard, Ora, additional, Anderson, Robin, additional, and Haupt, Ygal, additional

Published
2016
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206. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism

Author

Wang, Xiaoming, primary, Bey, Alexandra L., additional, Katz, Brittany M., additional, Badea, Alexandra, additional, Kim, Namsoo, additional, David, Lisa K., additional, Duffney, Lara J., additional, Kumar, Sunil, additional, Mague, Stephen D., additional, Hulbert, Samuel W., additional, Dutta, Nisha, additional, Hayrapetyan, Volodya, additional, Yu, Chunxiu, additional, Gaidis, Erin, additional, Zhao, Shengli, additional, Ding, Jin-Dong, additional, Xu, Qiong, additional, Chung, Leeyup, additional, Rodriguiz, Ramona M., additional, Wang, Fan, additional, Weinberg, Richard J., additional, Wetsel, William C., additional, Dzirasa, Kafui, additional, Yin, Henry, additional, and Jiang, Yong-hui, additional

Published
2016
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207. Abstract A72: The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling

Author

Mansour, Mariam, primary, Haupt, Sue, additional, Chan, Ai-Leen, additional, Godde, Nathan, additional, Rizzitelli, Alexandra, additional, Loi, Sherene, additional, Caramia, Franco, additional, Deb, Siddartha, additional, Takano, Elena A., additional, Bishton, Mark, additional, Johnstone, Cameron, additional, Levav-Cohen, Yarra, additional, Jiang, Yong-Hui, additional, Yap, Alpha S., additional, Fox, Stephen, additional, Bernard, Ora, additional, Anderson, Robin, additional, and Haupt, Ygal, additional

Published
2016
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209. Therapeutic Approaches for Shankopathies

Author

Wang, Xiaoming, Bey, Alexandra L, Chung, Leeyup, Krystal, Andrew D, and Jiang, Yong-Hui

Subjects
Child Development Disorders, autism spectrum disorders, mouse model, Intellectual and Developmental Disabilities (IDD), Autism, Medical Physiology, brain stimulation, Nerve Tissue Proteins, Synaptic Transmission, Article, mental disorders, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Pervasive, Pediatric, Neurology & Neurosurgery, Neurosciences, Transcranial Magnetic Stimulation, Brain Disorders, body regions, Mental Health, Child Development Disorders, Pervasive, Mutation, synapses, Cognitive Sciences, SHANK family protein
Abstract

Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function.

Published
2013

210. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Author

Anagnostou, Evdokia, Cao, Dandan, Drmic, Irene E., Jiang, Yong-hui, Marshall, Christian R., Luo, Jun, Chrysler, Christina, Wang, Mingbang, Yuen, Ryan K.C., Lau, Lynette, Howe, Jennifer L., Carter, Melissa T., Lajonchere, Clara, Walker, Susan, Ring, Robert H., Wang, Guangbiao, He, Mingze, Nalpathamkalam, Thomas, Shi, Yujian, Ju, Jia, Mei, Junpu, Uddin, Mohammed, Thiruvahindrapuram, Bhooma, Chen, Nong, Wang, Jian, Thompson, Ann, Liang, Jieqin, Jin, Xin, Wu, Xueli, Zwaigenbaum, Lonnie, Merico, Daniele, and Wang, Zhe

Subjects
mental disorders
Abstract

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

Published
2013
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211. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3

Author

Pan, Yanzhen, Bousquet-Moore, Danielle, McCoy, Portia A., Beaudet, Arthur L., Kim, Caroline J., Lorenzo, Isabel, Ehlers, Michael D., Philpot, Benjamin D., Weinberg, Richard J., Berrios, Janet, Wu, Gangyi, Wang, Xiaoming, Rodriguiz, Ramona M., Colvin, Jennifer S., Jiang, Yong-hui, Wetsel, William C., Roberts, Adam C., and Je, H. Shawn

Abstract

SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan–McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4–9. Isoform-specific Shank3e4–9 homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3e4–9 male mice display more severe impairments than females in motor coordination. Shank3e4–9 mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3e4–9 mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.

Published
2011
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212. Quinidine in the treatment of KCNT1-positive epilepsies

Author

Mikati, Mohamad A, primary, Jiang, Yong-hui, additional, Carboni, Michael, additional, Shashi, Vandana, additional, Petrovski, Slave, additional, Spillmann, Rebecca, additional, Milligan, Carol J., additional, Li, Melody, additional, Grefe, Annette, additional, McConkie, Allyn, additional, Berkovic, Samuel, additional, Scheffer, Ingrid, additional, Mullen, Saul, additional, Bonner, Melanie, additional, Petrou, Steven, additional, and Goldstein, David, additional

Published
2015
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213. De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Author

Tanaka, Akemi J., primary, Cho, Megan T., additional, Retterer, Kyle, additional, Jones, Julie R., additional, Nowak, Catherine, additional, Douglas, Jessica, additional, Jiang, Yong-Hui, additional, McConkie-Rosell, Allyn, additional, Schaefer, G. Bradley, additional, Kaylor, Julie, additional, Rahman, Omar A., additional, Telegrafi, Aida, additional, Friedman, Bethany, additional, Douglas, Ganka, additional, Monaghan, Kristin G., additional, and Chung, Wendy K., additional

Published
2015
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214. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

Author

Zhu, Xiaolin, primary, Petrovski, Slavé, additional, Xie, Pingxing, additional, Ruzzo, Elizabeth K., additional, Lu, Yi-Fan, additional, McSweeney, K. Melodi, additional, Ben-Zeev, Bruria, additional, Nissenkorn, Andreea, additional, Anikster, Yair, additional, Oz-Levi, Danit, additional, Dhindsa, Ryan S., additional, Hitomi, Yuki, additional, Schoch, Kelly, additional, Spillmann, Rebecca C., additional, Heimer, Gali, additional, Marek-Yagel, Dina, additional, Tzadok, Michal, additional, Han, Yujun, additional, Worley, Gordon, additional, Goldstein, Jennifer, additional, Jiang, Yong-Hui, additional, Lancet, Doron, additional, Pras, Elon, additional, Shashi, Vandana, additional, McHale, Duncan, additional, Need, Anna C., additional, and Goldstein, David B., additional

Published
2015
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215. Exome sequencing results in successful riboflavin treatment of a rapidly progressive neurological condition

Author

Petrovski, Slavé, primary, Shashi, Vandana, additional, Petrou, Steven, additional, Schoch, Kelly, additional, McSweeney, Keisha Melodi, additional, Dhindsa, Ryan S., additional, Krueger, Brian, additional, Crimian, Rebecca, additional, Case, Laura E., additional, Khalid, Roha, additional, El-Dairi, Maysantoine A., additional, Jiang, Yong-Hui, additional, Mikati, Mohamad A., additional, and Goldstein, David B., additional

Published
2015
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217. Adult Surgical Experience With Loeys-Dietz Syndrome

Author

Williams, Jason A., primary, Hanna, Jennifer M., additional, Shah, Asad A., additional, Andersen, Nicholas D., additional, McDonald, Marie T., additional, Jiang, Yong-hui, additional, Wechsler, Stephanie Burns, additional, Zomorodi, Ali, additional, McCann, Richard L., additional, and Hughes, G. Chad, additional

Published
2015
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218. A CACNA1C Variant Associated with Reduced Voltage-Dependent Inactivation, Increased Ca(V)1.2 Channel Window Current, and Arrhythmogenesis

Author

Hennessey, Jessica A., Boczek, Nicole J., Jiang, Yong-Hui, Miller, Joelle D., Patrick, William, Pfeiffer, Ryan, Sutphin, Brittan S., Tester, David J., Barajas-Martinez, Hector, Ackerman, Michael J., Antzelevitch, Charles, Kanter, Ronald, Pitt, Geoffrey S., Hennessey, Jessica A., Boczek, Nicole J., Jiang, Yong-Hui, Miller, Joelle D., Patrick, William, Pfeiffer, Ryan, Sutphin, Brittan S., Tester, David J., Barajas-Martinez, Hector, Ackerman, Michael J., Antzelevitch, Charles, Kanter, Ronald, and Pitt, Geoffrey S.

Abstract

Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of CaV1.2 c

Published
2014
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219. A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network.

Author

Spillmann, Rebecca C., McConkie-Rosell, Allyn, Pena, Loren, Yong-Hui Jiang, Schoch, Kelly, Walley, Nicole, Sanders, Camilla, Sullivan, Jennifer, Hooper, Stephen R., Shashi, Vandana, Jiang, Yong-Hui, and Undiagnosed Diseases Network

Subjects
DIAGNOSIS, HEALTH of patients, PHYSICIAN-patient relations, NARRATIVE medicine, MEDICAL ethics, RESEARCH funding, QUALITATIVE research, SYMPTOMS
Abstract

Background: Patients' stories of their illnesses help bridge the divide between patients and providers, facilitating more humane medical care. Illness narratives have been classified into three types: restitution (expectation of recovery), chaos (suffering and loss), and quest (unexpected positive effect from illness). Undiagnosed patients have unique illness experiences and obtaining their narratives would provide insights into the medical and emotional impact of living with an undiagnosed illness. Adults and children with undiagnosed diseases apply to be evaluated by the Undiagnosed Diseases Network (UDN). Written illness narratives from 40 UDN applicants, including 20 adult probands who applied for themselves and 20 parents who applied for their children, were analyzed for: 1) narrative content and 2) narrative type.Results: Narrative content: could be grouped into three themes: 1) Expectations of the UDN: the majority felt they had no further healthcare options and hoped the UDN would provide them with a diagnosis, with the adults expecting to return to their previously healthy life and the parents wanting information to manage their child's healthcare. 2) Personal medical information: the narratives reported worsening of symptoms and some offered opinions regarding the cause of their illness. The proband narratives had few objective findings, while parental narratives had detailed objective information. 3) Experiences related to living with their undiagnosed illness: frustration at being undiagnosed was expressed. The adults felt they had to provide validation of their symptoms to providers, given the lack of objective findings. The parents worried that something relevant to their child's management was being overlooked. Narrative type: All the narratives were of the chaos type, but for different reasons, with the probands describing loss and suffering and the parents expressing fear for their child's future. The parental narratives also had elements of restitution and quest, with acceptance of "a new normal", and an emphasis on the positive aspects of their child's illness which was absent from the probands.Conclusions: These narratives illustrate the chaos that coexists with being undiagnosed. The differences between the proband and parental narratives suggest that these two groups have different needs that need to be considered during their evaluation and management. [ABSTRACT FROM AUTHOR]

Published
2017
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220. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

Author

Mulkey, Sarah B., Ben‐Zeev, Bruria, Nicolai, Joost, Carroll, John L., Grønborg, Sabine, Jiang, Yong‐hui, Joshi, Nishtha, Kelly, Megan, Koolen, David. A., Mikati, Mohamad A., Park, Kristen, Pearl, Phillip L., Scheffer, Ingrid E., Spillmann, Rebecca C., Taglialatela, Maurizio, Vieker, Silvia, Weckhuysen, Sarah, Cooper, Edward C., and Cilio, Maria Roberta

Subjects
MYOCLONUS, EPILEPSY, SPASMS, MERRF syndrome, ELECTROENCEPHALOGRAPHY, DIAGNOSIS of brain diseases
Abstract

Objective To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro , have a distinct clinical presentation and outcome. Methods Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board ( IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. Results Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography ( EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. Significance Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Published
2017
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221. A CACNA1C Variant Associated with Reduced Voltage-Dependent Inactivation, Increased CaV1.2 Channel Window Current, and Arrhythmogenesis

Author

Hennessey, Jessica A., primary, Boczek, Nicole J., additional, Jiang, Yong-Hui, additional, Miller, Joelle D., additional, Patrick, William, additional, Pfeiffer, Ryan, additional, Sutphin, Brittan S., additional, Tester, David J., additional, Barajas-Martinez, Hector, additional, Ackerman, Michael J., additional, Antzelevitch, Charles, additional, Kanter, Ronald, additional, and Pitt, Geoffrey S., additional

Published
2014
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224. A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

Author

Du, Xiaonan, primary, An, Yu, additional, Yu, Lifei, additional, Liu, Renchao, additional, Qin, Yanrong, additional, Guo, Xiaohong, additional, Sun, Daokan, additional, Zhou, Shuizhen, additional, Wu, Bailin, additional, Jiang, Yong-hui, additional, and Wang, Yi, additional

Published
2014
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227. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing

Author

Jiang, Yong-hui, Yuen, Ryan K.C., Wang, Mingbang, Jin, Xin, Chen, Nong, Wu, Xueli, Ju, Jia, Mei, Junpu, Shi, Yujian, He, Mingze, Wang, Guangbiao, Liang, Jieqin, Wang, Zhe, Cao, Dandan, Carter, Melissa T., Chrysler, Christina, Drmic, Irene E., Howe, Jennifer L., Lau, Lynette, Marshall, Christian R., Merico, Daniele, Nalpathamkalam, Thomas, Thiruvahindrapuram, Bhooma, Thompson, Ann, Uddin, Mohammed, Walker, Susan, Luo, Jun, Anagnostou, Evdokia, Zwaigenbaum, Lonnie, Ring, Robert H., Wang, Jian, Lajonchere, Clara, Wang, Jun, Shih, Andy, Szatmari, Peter, Yang, Huanming, Dawson, Geraldine, Li, Yingrui, Scherer, Stephen W., Jiang, Yong-hui, Yuen, Ryan K.C., Wang, Mingbang, Jin, Xin, Chen, Nong, Wu, Xueli, Ju, Jia, Mei, Junpu, Shi, Yujian, He, Mingze, Wang, Guangbiao, Liang, Jieqin, Wang, Zhe, Cao, Dandan, Carter, Melissa T., Chrysler, Christina, Drmic, Irene E., Howe, Jennifer L., Lau, Lynette, Marshall, Christian R., Merico, Daniele, Nalpathamkalam, Thomas, Thiruvahindrapuram, Bhooma, Thompson, Ann, Uddin, Mohammed, Walker, Susan, Luo, Jun, Anagnostou, Evdokia, Zwaigenbaum, Lonnie, Ring, Robert H., Wang, Jian, Lajonchere, Clara, Wang, Jun, Shih, Andy, Szatmari, Peter, Yang, Huanming, Dawson, Geraldine, Li, Yingrui, and Scherer, Stephen W.

Published
2013

228. Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1Eand literature review

Author

Duffney, Lara J., Valdez, Purnima, Tremblay, Martine W., Cao, Xinyu, Montgomery, Sarah, McConkie‐Rosell, Allyn, and Jiang, Yong‐hui

Abstract

Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10‐year‐old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3′ end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy‐terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1Ein intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1Ecauses autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development.

Published
2018
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229. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases

Author

Pena, Loren D M, Jiang, Yong-Hui, Schoch, Kelly, Spillmann, Rebecca C, Walley, Nicole, Stong, Nicholas, Rapisardo Horn, Sarah, Sullivan, Jennifer A, McConkie-Rosell, Allyn, Kansagra, Sujay, Smith, Edward C, El-Dairi, Mays, Bellet, Jane, Keels, Martha Ann, Jasien, Joan, Kranz, Peter G, Noel, Richard, Nagaraj, Shashi K, Lark, Robert K, Wechsler, Daniel S G, del Gaudio, Daniela, Leung, Marco L, Hendon, Laura G, Parker, Collette C, Jones, Kelly L, Goldstein, David B, and Shashi, Vandana

Abstract

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

Published
2018
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233. Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome.

Author

Su, Hailing, Su, Hailing, Fan, Weiwei, Coskun, Pinar E, Vesa, Jouni, Gold, June-Anne, Jiang, Yong-Hui, Potluri, Prasanth, Procaccio, Vincent, Acab, Allan, Weiss, John H, Wallace, Douglas C, Kimonis, Virginia E, Su, Hailing, Su, Hailing, Fan, Weiwei, Coskun, Pinar E, Vesa, Jouni, Gold, June-Anne, Jiang, Yong-Hui, Potluri, Prasanth, Procaccio, Vincent, Acab, Allan, Weiss, John H, Wallace, Douglas C, and Kimonis, Virginia E

Abstract

Angelman syndrome (AS) is a severe neurological disorder caused by a deficiency of ubiquitin protein ligase E3A (UBE3A), but the pathophysiology of the disease remains unknown. We now report that in the brains of AS mice in which the maternal UBE3A allele is mutated (m-) and the paternal allele is potentially inactivated by imprinting (p+) (UBE3A m-\p+), the mitochondria are abnormal and exhibit a partial oxidative phosphorylation (OXPHOS) defect. Electron microscopy of the hippocampal region of the UBE3A m-\p+ mice (n=6) reveals small, dense mitochondria with altered cristae, relative to wild-type littermates (n=6) and reduced synaptic vesicle density. The specific activity of OXPHOS complex III is reduced in whole brain mitochondria in UBE3A m-\p+ (n=5) mice versus wild-type littermates (n=5). Therefore, mitochondrial dysfunction may contribute to the pathophysiology of Angelman syndrome.

Published
2011

236. Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy

Author

Ruzzo, Elizabeth K., primary, Capo-Chichi, José-Mario, additional, Ben-Zeev, Bruria, additional, Chitayat, David, additional, Mao, Hanqian, additional, Pappas, Andrea L., additional, Hitomi, Yuki, additional, Lu, Yi-Fan, additional, Yao, Xiaodi, additional, Hamdan, Fadi F., additional, Pelak, Kimberly, additional, Reznik-Wolf, Haike, additional, Bar-Joseph, Ifat, additional, Oz-Levi, Danit, additional, Lev, Dorit, additional, Lerman-Sagie, Tally, additional, Leshinsky-Silver, Esther, additional, Anikster, Yair, additional, Ben-Asher, Edna, additional, Olender, Tsviya, additional, Colleaux, Laurence, additional, Décarie, Jean-Claude, additional, Blaser, Susan, additional, Banwell, Brenda, additional, Joshi, Rasesh B., additional, He, Xiao-Ping, additional, Patry, Lysanne, additional, Silver, Rachel J., additional, Dobrzeniecka, Sylvia, additional, Islam, Mohammad S., additional, Hasnat, Abul, additional, Samuels, Mark E., additional, Aryal, Dipendra K., additional, Rodriguiz, Ramona M., additional, Jiang, Yong-hui, additional, Wetsel, William C., additional, McNamara, James O., additional, Rouleau, Guy A., additional, Silver, Debra L., additional, Lancet, Doron, additional, Pras, Elon, additional, Mitchell, Grant A., additional, Michaud, Jacques L., additional, and Goldstein, David B., additional

Published
2013
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238. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Author

Jiang, Yong-hui, primary, Yuen, Ryan K.C., additional, Jin, Xin, additional, Wang, Mingbang, additional, Chen, Nong, additional, Wu, Xueli, additional, Ju, Jia, additional, Mei, Junpu, additional, Shi, Yujian, additional, He, Mingze, additional, Wang, Guangbiao, additional, Liang, Jieqin, additional, Wang, Zhe, additional, Cao, Dandan, additional, Carter, Melissa T., additional, Chrysler, Christina, additional, Drmic, Irene E., additional, Howe, Jennifer L., additional, Lau, Lynette, additional, Marshall, Christian R., additional, Merico, Daniele, additional, Nalpathamkalam, Thomas, additional, Thiruvahindrapuram, Bhooma, additional, Thompson, Ann, additional, Uddin, Mohammed, additional, Walker, Susan, additional, Luo, Jun, additional, Anagnostou, Evdokia, additional, Zwaigenbaum, Lonnie, additional, Ring, Robert H., additional, Wang, Jian, additional, Lajonchere, Clara, additional, Wang, Jun, additional, Shih, Andy, additional, Szatmari, Peter, additional, Yang, Huanming, additional, Dawson, Geraldine, additional, Li, Yingrui, additional, and Scherer, Stephen W., additional

Published
2013
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239. c-Abl Phosphorylates E6AP and Regulates Its E3 Ubiquitin Ligase Activity

Author

Chan, Ai-Leen, primary, Grossman, Tamar, additional, Zuckerman, Valentina, additional, Campigli Di Giammartino, Dafne, additional, Moshel, Ofra, additional, Scheffner, Martin, additional, Monahan, Brendon, additional, Pilling, Pat, additional, Jiang, Yong-Hui, additional, Haupt, Sue, additional, Schueler-Furman, Ora, additional, and Haupt, Ygal, additional

Published
2013
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241. Not the End of the Odyssey: Parental Perceptions of Whole Exome Sequencing (WES) in Pediatric Undiagnosed Disorders.

Author

Rosell, Allyn, Pena, Loren, Schoch, Kelly, Spillmann, Rebecca, Sullivan, Jennifer, Hooper, Stephen, Jiang, Yong-Hui, Mathey-Andrews, Nicolas, Goldstein, David, and Shashi, Vandana

Abstract

Due to the lack of empirical information on parental perceptions of primary results of whole exome sequencing (WES), we conducted a retrospective semi-structured interview with 19 parents of children who had undergone WES. Perceptions explored during the interview included factors that would contribute to parental empowerment such as: parental expectations, understanding of the WES and results, utilization of the WES information, and communication of findings to health/educational professionals and family members. Results of the WES had previously been communicated to families within a novel framework of clinical diagnostic categories: 5/19 had Definite diagnoses, 6/19 had Likely diagnoses, 3/19 had Possible diagnosis and 5/19 had No diagnosis. All parents interviewed expressed a sense of duty to pursue the WES in search of a diagnosis; however, their expectations were tempered by previous experiences with negative genetic testing results. Approximately half the parents worried that a primary diagnosis that would be lethal might be identified; however, the hope of a diagnosis outweighed this concern. Parents were accurately able to summarize their child's WES findings, understood the implications for recurrence risks, and were able to communicate these findings to family and medical/educational providers. The majority of those with a Definite/Likely diagnosis felt that their child's medical care was more focused, or there was a reduction in worry, despite the lack of a specific treatment. Irrespective of diagnostic outcome, parents recommended that follow-up visits be built into the process. Several parents expressed a desire to have all variants of unknown significance (VUS) reported to them so that they could investigate these themselves. Finally, for some families whose children had a Definite/Likely diagnosis, there was remaining frustration and a sense of isolation, due to the limited information that was available about the diagnosed rare disorders and the inability to connect to other families, suggesting that for families with rare genetic disorders, the diagnostic odyssey does not necessarily end with a diagnosis. Qualitative interviewing served a meaningful role in eliciting new information about parental motivations, expectations, and knowledge of WES. Our findings highlight a need for continued communication with families as we navigate the new landscape of genomic sequencing. [ABSTRACT FROM AUTHOR]

Published
2016
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244. E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis

Author

Wolyniec, Kamil, primary, Shortt, Jake, additional, de Stanchina, Elisa, additional, Levav-Cohen, Yaara, additional, Alsheich-Bartok, Osnat, additional, Louria-Hayon, Igal, additional, Corneille, Vincent, additional, Kumar, Beena, additional, Woods, Simone J., additional, Opat, Stephen, additional, Johnstone, Ricky W., additional, Scott, Clare L., additional, Segal, David, additional, Pandolfi, Pier Paolo, additional, Fox, Stephen, additional, Strasser, Andreas, additional, Jiang, Yong-Hui, additional, Lowe, Scott W., additional, Haupt, Sue, additional, and Haupt, Ygal, additional

Published
2012
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246. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Author

Kim, Yuna, Lee, Hyeong-Min, Xiong, Yan, Sciaky, Noah, Hulbert, Samuel W, Cao, Xinyu, Everitt, Jeffrey I, Jin, Jian, Roth, Bryan L, and Jiang, Yong-hui

Abstract

Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642—two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)—activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS−U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS−Unewborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.

Published
2017
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247. Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome

Author

Su, Hailing, primary, Fan, Weiwei, additional, Coskun, Pinar E., additional, Vesa, Jouni, additional, Gold, June-Anne, additional, Jiang, Yong-Hui, additional, Potluri, Prasanth, additional, Procaccio, Vincent, additional, Acab, Allan, additional, Weiss, John H., additional, Wallace, Douglas C., additional, and Kimonis, Virginia E., additional

Published
2011
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250. Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

Author

Rice, Gillian, primary, Patrick, Teresa, additional, Parmar, Rekha, additional, Taylor, Claire F., additional, Aeby, Alec, additional, Aicardi, Jean, additional, Artuch, Rafael, additional, Montalto, Simon Attard, additional, Bacino, Carlos A., additional, Barroso, Bruno, additional, Baxter, Peter, additional, Benko, Willam S., additional, Bergmann, Carsten, additional, Bertini, Enrico, additional, Biancheri, Roberta, additional, Blair, Edward M., additional, Blau, Nenad, additional, Bonthron, David T., additional, Briggs, Tracy, additional, Brueton, Louise A., additional, Brunner, Han G., additional, Burke, Christopher J., additional, Carr, Ian M., additional, Carvalho, Daniel R., additional, Chandler, Kate E., additional, Christen, Hans-Jürgen, additional, Corry, Peter C., additional, Cowan, Frances M., additional, Cox, Helen, additional, D’Arrigo, Stefano, additional, Dean, John, additional, De Laet, Corinne, additional, De Praeter, Claudine, additional, Déry, Catherine, additional, Ferrie, Colin D., additional, Flintoff, Kim, additional, Frints, Suzanna G.M., additional, Garcia-Cazorla, Angels, additional, Gener, Blanca, additional, Goizet, Cyril, additional, Goutières, Françoise, additional, Green, Andrew J., additional, Guët, Agnès, additional, Hamel, Ben C.J., additional, Hayward, Bruce E., additional, Heiberg, Arvid, additional, Hennekam, Raoul C., additional, Husson, Marie, additional, Jackson, Andrew P., additional, Jayatunga, Rasieka, additional, Jiang, Yong-Hui, additional, Kant, Sarina G., additional, Kao, Amy, additional, King, Mary D., additional, Kingston, Helen M., additional, Klepper, Joerg, additional, van der Knaap, Marjo S., additional, Kornberg, Andrew J., additional, Kotzot, Dieter, additional, Kratzer, Wilfried, additional, Lacombe, Didier, additional, Lagae, Lieven, additional, Landrieu, Pierre Georges, additional, Lanzi, Giovanni, additional, Leitch, Andrea, additional, Lim, Ming J., additional, Livingston, John H., additional, Lourenco, Charles M., additional, Lyall, E. G. Hermione, additional, Lynch, Sally A., additional, Lyons, Michael J., additional, Marom, Daphna, additional, McClure, John P., additional, McWilliam, Robert, additional, Melancon, Serge B., additional, Mewasingh, Leena D., additional, Moutard, Marie-Laure, additional, Nischal, Ken K., additional, Østergaard, John R., additional, Prendiville, Julie, additional, Rasmussen, Magnhild, additional, Rogers, R. Curtis, additional, Roland, Dominique, additional, Rosser, Elisabeth M., additional, Rostasy, Kevin, additional, Roubertie, Agathe, additional, Sanchis, Amparo, additional, Schiffmann, Raphael, additional, Scholl-Bürgi, Sabine, additional, Seal, Sunita, additional, Shalev, Stavit A., additional, Corcoles, C. Sierra, additional, Sinha, Gyan P., additional, Soler, Doriette, additional, Spiegel, Ronen, additional, Stephenson, John B.P., additional, Tacke, Uta, additional, Tan, Tiong Yang, additional, Till, Marianne, additional, Tolmie, John L., additional, Tomlin, Pam, additional, Vagnarelli, Federica, additional, Valente, Enza Maria, additional, Van Coster, Rudy N.A., additional, Van der Aa, Nathalie, additional, Vanderver, Adeline, additional, Vles, Johannes S.H., additional, Voit, Thomas, additional, Wassmer, Evangeline, additional, Weschke, Bernhard, additional, Whiteford, Margo L., additional, Willemsen, Michel A.A., additional, Zankl, Andreas, additional, Zuberi, Sameer M., additional, Orcesi, Simona, additional, Fazzi, Elisa, additional, Lebon, Pierre, additional, and Crow, Yanick J., additional

Published
2007
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