20 results on '"Andrews, Jonathan C."'
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2. De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features
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Acosta, Maria T., Adam, Margaret, Adams, David R., Alvarez, Raquel L., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Goddard, Page C., Godfrey, Rena A., Golden-Grant, Katie, Grajewski, Alana, Hadley, Don, Hahn, Sihoun, Halley, Meghan C., Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Kennedy, Jennifer, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Kozuira, Mary, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Mulvihill, John, Nakano-Okuno, Mariko, Nelson, Stanley F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Scott, C. Ron, Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zhang, Zhe, Zuchner, Stephan, Andrews, Jonathan C., Mok, Jung-Wan, Kanca, Oguz, Jangam, Sharayu, Tifft, Cynthia, and Russell, Bianca E.
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- 2023
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3. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.
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Kanca, Oguz, Andrews, Jonathan C, Lee, Pei-Tseng, Patel, Chirag, Braddock, Stephen R, Slavotinek, Anne M, Cohen, Julie S, Gubbels, Cynthia S, Aldinger, Kimberly A, Williams, Judy, Indaram, Maanasa, Fatemi, Ali, Yu, Timothy W, Agrawal, Pankaj B, Vezina, Gilbert, Simons, Cas, Crawford, Joanna, Lau, C Christopher, Undiagnosed Diseases Network, Chung, Wendy K, Markello, Thomas C, Dobyns, William B, Adams, David R, Gahl, William A, Wangler, Michael F, Yamamoto, Shinya, Bellen, Hugo J, and Malicdan, May Christine V
- Subjects
Undiagnosed Diseases Network ,Cerebellum ,Animals ,Humans ,Drosophila melanogaster ,Epilepsy ,Nervous System Malformations ,Coloboma ,Microfilament Proteins ,Developmental Disabilities ,Amino Acid Sequence ,Sequence Homology ,Phenotype ,Mutation ,Adult ,Child ,Infant ,Infant ,Newborn ,Female ,Male ,Young Adult ,Body Dysmorphic Disorders ,Intellectual Disability ,WD40 Repeats ,CG12333 ,Drosophila ,WD40 repeats ,WDR37 domains ,bang sensitivity ,wdr37 ,Genetics ,Pediatric ,Rare Diseases ,Congenital Structural Anomalies ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Intellectual and Developmental Disabilities (IDD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
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- 2019
4. Comparative exploration of mammalian deafness gene homologues in the Drosophila auditory organ shows genetic correlation between insect and vertebrate hearing
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Sutton, Daniel C., primary, Andrews, Jonathan C., additional, Dolezal, Dylan M., additional, Park, Ye Jin, additional, Li, Hongjie, additional, Eberl, Daniel F., additional, Yamamoto, Shinya, additional, and Groves, Andrew K., additional
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- 2024
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5. Advances in Next-Generation Sequencing Technologies and Functional Investigation of Candidate Variants in Neurological and Behavioral Disorders
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Andrews, Jonathan C., primary, Wangler, Michael F., additional, Yamamoto, Shinya, additional, and Posey, Jennifer E., additional
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- 2021
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6. Ade novomissense variant inEZH1associated with developmental delay exhibits functional deficits inDrosophila melanogaster
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Jangam, Sharayu, Briere, Lauren C., Jay, Kristy, Andrews, Jonathan C, Walker, Melissa A., Rodan, Lance H., High, Frances A., Yamamoto, Shinya, Sweetser, David A., and Wangler, Michael
- Subjects
Article - Abstract
EZH1(Enhancer of Zeste, homolog 1), a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues.EZH1represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, whileEZH1has not yet been linked to any human disease. However, the paralogEZH2is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have ade novovariant inEZH1, p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. HumanEZH1/2are homologous to flyEnhancer of zeste E(z), an essential gene in flies, and the residue (A678 in humans, A691 inDrosophila) is conserved. To further study this variant, we obtainedDrosophilanull alleles and generated transgenic flies expressing wild-type(E(z)WT)and the variant(E(z)A691G). TheE(z)A691Gvariant led to hyper H3K27me3 while theE(z)WTdid not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotorin vivothe variant rescued null-lethality similar to wild-type but theE(z)A691Gflies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novelEZH1 de novovariant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact inDrosophila. Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies theE(z)A691Ghas some characteristics of partial loss-of-function which may suggest it is a more complex allelein vivo.
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- 2023
7. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia
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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, Krasnewich, Donna M., 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, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, 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, Pak, Stephen, 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, Kanca, Oguz, Andrews, Jonathan C., Lee, Pei-Tseng, Patel, Chirag, Braddock, Stephen R., Slavotinek, Anne M., Cohen, Julie S., Gubbels, Cynthia S., Aldinger, Kimberly A., Williams, Judy, Indaram, Maanasa, Fatemi, Ali, Yu, Timothy W., Agrawal, Pankaj B., Vezina, Gilbert, Simons, Cas, Crawford, Joanna, Chung, Wendy K., and Dobyns, William B.
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- 2019
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8. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders
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Guo, Hui, Bettella, Elisa, Marcogliese, Paul C., Zhao, Rongjuan, Andrews, Jonathan C., Nowakowski, Tomasz J., Willemsen, M.H., Bon, B.W. van, Rinne, T.K., Kleefstra, T., Brunner, H.G., Yntema, H.G., Nickerson, Deborah A., Bamshad, Michael J., Guo, Hui, Bettella, Elisa, Marcogliese, Paul C., Zhao, Rongjuan, Andrews, Jonathan C., Nowakowski, Tomasz J., Willemsen, M.H., Bon, B.W. van, Rinne, T.K., Kleefstra, T., Brunner, H.G., Yntema, H.G., Nickerson, Deborah A., and Bamshad, Michael J.
- Abstract
Contains fulltext : 208995.pdf (publisher's version ) (Open Access)
- Published
- 2019
9. Methyl-CpG binding domain proteins inhibit interspecies courtship and promote aggression in Drosophila
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Gupta, Tarun, primary, Morgan, Hannah R., additional, Andrews, Jonathan C., additional, Brewer, Edmond R., additional, and Certel, Sarah J., additional
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- 2017
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10. A comprehensive Drosophilaresource to identify key functional interactions between SARS-CoV-2 factors and host proteins
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Guichard, Annabel, Lu, Shenzhao, Kanca, Oguz, Bressan, Daniel, Huang, Yan, Ma, Mengqi, Sanz Juste, Sara, Andrews, Jonathan C., Jay, Kristy L., Sneider, Marketta, Schwartz, Ruth, Huang, Mei-Chu, Bei, Danqing, Pan, Hongling, Ma, Liwen, Lin, Wen-Wen, Auradkar, Ankush, Bhagwat, Pranjali, Park, Soo, Wan, Kenneth H., Ohsako, Takashi, Takano-Shimizu, Toshiyuki, Celniker, Susan E., Wangler, Michael F., Yamamoto, Shinya, Bellen, Hugo J., and Bier, Ethan
- Abstract
Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive DrosophilaCOVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that NSP8 engages in strong genetic interactions with several human candidates, most prominently with the ATE1 arginyltransferase to induce actin arginylation and cytoskeletal disorganization, and that two ATE1 inhibitors can reverse NSP8 phenotypes. The DCR enables parallel global-scale functional analysis of SARS-CoV-2 components in a prime genetic model system.
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- 2023
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11. A de novomissense variant in EZH1associated with developmental delay exhibits functional deficits in Drosophila melanogaster
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Jangam, Sharayu V, Briere, Lauren C, Jay, Kristy L, Andrews, Jonathan C, Walker, Melissa A, Rodan, Lance H, High, Frances A, Yamamoto, Shinya, Sweetser, David A, and Wangler, Michael F
- Abstract
EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1has not yet been linked to any human disease. However, the paralog EZH2is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novomissense variant in EZH1through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2are homologous to fly Enhancer of zeste(E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WTinduces homeotic patterning defects but notably the E(z)A691Gvariant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novovariant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.Human EZH1 has not been previously linked to human Mendelian disease. Here, Jangam, Briere, Jay et al.describe an individual with a de novo missense change in EZH1. An identical missense substitution in the paralog EZH2 has also been found in human Weaver syndrome. While Drosophilanull E(z) mutants are lethal, the authors use rescue and overexpression experiments to demonstrate that this EZH1 substitution appears to have biochemical gain-of-function characteristics.
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- 2023
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12. Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Drosophila Males
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Andrews, Jonathan C., primary, Fernández, María Paz, additional, Yu, Qin, additional, Leary, Greg P., additional, Leung, Adelaine K. W., additional, Kavanaugh, Michael P., additional, Kravitz, Edward A., additional, and Certel, Sarah J., additional
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- 2014
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13. De novo variants in MRTFBhave gain-of-function activity in Drosophilaand are associated with a novel neurodevelopmental phenotype with dysmorphic features
- Author
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Andrews, Jonathan C., Mok, Jung-Wan, Kanca, Oguz, Jangam, Sharayu, Tifft, Cynthia, Macnamara, Ellen F., Russell, Bianca E., Wang, Lee-kai, Acosta, Maria T., Adam, Margaret, Adams, David R., Alvarez, Raquel L., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Goddard, Page C., Godfrey, Rena A., Golden-Grant, Katie, Grajewski, Alana, Hadley, Don, Hahn, Sihoun, Halley, Meghan C., Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Kennedy, Jennifer, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Kozuira, Mary, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Mulvihill, John, Nakano-Okuno, Mariko, Nelson, Stanley F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina G.S., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Scott, C. Ron, Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Hubshman, Monika Weisz, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zhang, Zhe, Zuchner, Stephan, Nelson, Stanley F., Bellen, Hugo J., Yamamoto, Shinya, Malicdan, May Christine V., and Wangler, Michael F.
- Abstract
Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder.
- Published
- 2023
- Full Text
- View/download PDF
14. The Roles of the Pastor in the Interdisciplinary Rehabilitation Team
- Author
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Easton, Kristen L., primary and Andrews, Jonathan C., additional
- Published
- 2000
- Full Text
- View/download PDF
15. Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Drosophila Males.
- Author
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Andrews, Jonathan C., Fernández, María Paz, Yu, Qin, Leary, Greg P., Leung, Adelaine K. W., Kavanaugh, Michael P., Kravitz, Edward A., and Certel, Sarah J.
- Subjects
- *
OCTOPAMINE , *SYNAPSES , *CHEMORECEPTORS , *DROSOPHILA genetics , *ANIMAL social behavior , *NEURONS , *INSECTS - Abstract
Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-FruM neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
16. Nursing the Soul
- Author
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Easton, Kristen L., primary and Andrews, Jonathan C., additional
- Published
- 1999
- Full Text
- View/download PDF
17. A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster.
- Author
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Jangam, Sharayu V., Briere, Lauren C., Jay, Kristy L., Andrews, Jonathan C., Walker, Melissa A., Rodan, Lance H., High, Frances A., Yamamoto, Shinya, Sweetser, David A., and Wangler, Michael F.
- Subjects
- *
GENETIC mutation , *ANIMAL experimentation , *WESTERN immunoblotting , *GENETIC variation , *DEVELOPMENTAL disabilities , *GENE expression profiling , *INSECTS - Abstract
EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features.
- Author
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Andrews JC, Mok JW, Kanca O, Jangam S, Tifft C, Macnamara EF, Russell BE, Wang LK, Nelson SF, Bellen HJ, Yamamoto S, Malicdan MCV, and Wangler MF
- Subjects
- Animals, Child, Humans, Drosophila genetics, Actins genetics, Gain of Function Mutation, Transcription Factors genetics, Phenotype, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Purpose: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder., Methods: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB., Results: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFB
R104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton., Conclusion: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
19. A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster .
- Author
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Jangam S, Briere LC, Jay K, Andrews JC, Walker MA, Rodan LH, High FA, Yamamoto S, Sweetser DA, and Wangler M
- Abstract
EZH1 ( Enhancer of Zeste, homolog 1) , a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues. EZH1 represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo variant in EZH1 , p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. Human EZH1 / 2 are homologous to fly Enhancer of zeste E(z) , an essential gene in flies, and the residue (A678 in humans, A691 in Drosophila ) is conserved. To further study this variant, we obtained Drosophila null alleles and generated transgenic flies expressing wild-type (E(z)
WT ) and the variant (E(z)A691G ) . The E(z)A691G variant led to hyper H3K27me3 while the E(z)WT did not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotor in vivo the variant rescued null-lethality similar to wild-type but the E(z)A691G flies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila . Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies the E(z)A691G has some characteristics of partial loss-of-function which may suggest it is a more complex allele in vivo .- Published
- 2023
- Full Text
- View/download PDF
20. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.
- Author
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Guo H, Bettella E, Marcogliese PC, Zhao R, Andrews JC, Nowakowski TJ, Gillentine MA, Hoekzema K, Wang T, Wu H, Jangam S, Liu C, Ni H, Willemsen MH, van Bon BW, Rinne T, Stevens SJC, Kleefstra T, Brunner HG, Yntema HG, Long M, Zhao W, Hu Z, Colson C, Richard N, Schwartz CE, Romano C, Castiglia L, Bottitta M, Dhar SU, Erwin DJ, Emrick L, Keren B, Afenjar A, Zhu B, Bai B, Stankiewicz P, Herman K, Mercimek-Andrews S, Juusola J, Wilfert AB, Abou Jamra R, Büttner B, Mefford HC, Muir AM, Scheffer IE, Regan BM, Malone S, Gecz J, Cobben J, Weiss MM, Waisfisz Q, Bijlsma EK, Hoffer MJV, Ruivenkamp CAL, Sartori S, Xia F, Rosenfeld JA, Bernier RA, Wangler MF, Yamamoto S, Xia K, Stegmann APA, Bellen HJ, Murgia A, and Eichler EE
- Subjects
- Adolescent, Adult, Animals, Autistic Disorder genetics, Autistic Disorder psychology, Behavior, Animal, Brain metabolism, Child, Child, Preschool, Craniofacial Abnormalities genetics, Developmental Disabilities genetics, Developmental Disabilities psychology, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster, Epilepsy genetics, Female, Humans, Intellectual Disability genetics, Intellectual Disability psychology, Language Development Disorders genetics, Language Development Disorders psychology, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mental Disorders psychology, Muscle Proteins genetics, Muscle Proteins metabolism, Mutation, Neurodevelopmental Disorders psychology, Neuroglia metabolism, Neurons metabolism, Proteins metabolism, Exome Sequencing, Young Adult, Mental Disorders genetics, Nerve Tissue Proteins metabolism, Neurodevelopmental Disorders genetics, Proteins genetics
- Abstract
Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
- Published
- 2019
- Full Text
- View/download PDF
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