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1. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, Elizabeth, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan, Chedrawi, Aziza, Hashem, Mais, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer, Sands, Tristan, Wilson, Golder, Silvertooth, Erin, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein, Ockeloen, Charlotte, Pfundt, Rolph, Kroft, Sanne, Field, Michael, Laranjeira, Francisco, Fortuna, Ana, Soares, Ana, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David, Bird, Lynne, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe, Blazo, Maria, Bijlsma, Emilia, Rosenfeld, Jill, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb, Armstrong, Ruth, and Kalscheuer, Vera

Subjects
Male, Female, Humans, Neurodevelopmental Disorders, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

2. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Author

Johnson, Brett V, Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A, VanHasselt, Peter M, Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pena, Loren, Shashi, Vandana, Undiagnosed Diseases Network, Schoch, Kelly, Sullivan, Jennifer A, Pinto E Vairo, Filippo, Pichurin, Pavel N, Ewing, Sarah A, Barnett, Sarah S, Klee, Eric W, Perry, M Scott, Koenig, Mary Kay, Keegan, Catherine E, Schuette, Jane L, Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D, Rosenfeld, Jill A, Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E, Steeves, Marcie A, Hollander, Nicolette den, Hoffer, Mariëtte JV, Reijnders, Margot RF, Demirdas, Serwet, Koboldt, Daniel C, Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E, Shieh, Christine, Sanchez-Lara, Pedro A, Graham, John M, Tezcan, Kamer, Schaefer, GB, Danylchuk, Noelle R, Asamoah, Alexander, Jackson, Kelly E, Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A, and Kleefstra, Tjitske

Subjects
Undiagnosed Diseases Network, Animals, Humans, Mice, Ubiquitin Thiolesterase, Transforming Growth Factor beta, Developmental Disabilities, Signal Transduction, Phenotype, Female, Male, Haploinsufficiency, Intellectual Disability, Brain malformation, Deubiquitylating enzyme, Hippocampus, Neurodevelopmental disorder, TGFβ, USP9X, Congenital Structural Anomalies, Genetics, Neurosciences, Pediatric, Mental Health, Behavioral and Social Science, Brain Disorders, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, TGF beta, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

Published
2020

3. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

Author

Pena, Loren, Shashi, Vandana, Schoch, Kelly, Sullivan, Jennifer A., Acosta, Maria T., Adams, David R., Aday, Aaron, Alejandro, Mercedes E., Allard, Patrick, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Barbouth, Deborah, Batzli, Gabriel F., Beggs, Alan H., Bellen, Hugo J., Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bick, David P., Birch, Camille L., Bivona, Stephanie, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brokamp, Elly, Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Carrasquillo, Olveen, Peter Chang, Ta Chen, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D'Souza, Precilla, Dasari, Surendra, Davids, Mariska, Davidson, Jean M., Dayal, Jyoti G., Dell'Angelica, Esteban C., Dhar, Shweta U., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Dries, Annika M., Duncan, Laura, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Enns, Gregory M., Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Friedman, Noah D., Gahl, William A., Godfrey, Rena A., Goldman, Alica M., Goldstein, David B., Gourdine, Jean-Philippe F., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., High, Frances, 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., 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, 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., Markello, Thomas C., Marom, Ronit, Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Merker, Jason D., 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., Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Renteri, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rowley, Robb K., Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Shakachite, Lisa, Sharma, Prashant, Shields, Kathleen, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Solnica-Krezel, Lilianna, Spillmann, Rebecca C., Stoler, Joan M., Stong, Nicholas, Sweetser, David A., Tamburro, Cecelia P., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Vogel, Tiphanie P., Waggott, Daryl M., 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, Gahl, William, Johnson, Brett V., Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A., VanHasselt, Peter M., Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pinto e Vairo, Filippo, Pichurin, Pavel N., Ewing, Sarah A., Barnett, Sarah S., Klee, Eric W., Perry, M. Scott, Koenig, Mary Kay, Keegan, Catherine E., Schuette, Jane L., Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D., Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E., Steeves, Marcie A., Hollander, Nicolette den, Hoffer, Mariëtte J.V., Reijnders, Margot R.F., Demirdas, Serwet, Koboldt, Daniel C., Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E., Shieh, Christine, Sanchez-Lara, Pedro A., Graham, John M., Jr., Tezcan, Kamer, Schaefer, G.B., Danylchuk, Noelle R., Asamoah, Alexander, Jackson, Kelly E., Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A., Kleefstra, Tjitske, Penzes, Peter, Wood, Stephen A., Burne, Thomas, Pierson, Tyler Mark, Piper, Michael, Gécz, Jozef, and Jolly, Lachlan A.

Published
2020
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4. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., Ozanturk, Aysegul, Rodríguez Criado, Germán, Grasshoff, Ute, de Hoon, Bas, Field, Michael, Manouvrier-Hanu, Sylvie, E. Hickey, Scott, Kammoun, Molka, Gripp, Karen W., Bauer, Claudia, Schroeder, Christopher, Toutain, Annick, Mihalic Mosher, Theresa, Kelly, Benjamin J., White, Peter, Dufke, Andreas, Rentmeester, Eveline, Moon, Sungjin, Koboldt, Daniel C, van Roozendaal, Kees E. P., Hu, Hao, Haas, Stefan A., Ropers, Hans-Hilger, Murray, Lucinda, Haan, Eric, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Liebelt, Jan, Hobson, Lynne, De Rademaeker, Marjan, Geraedts, Joep, Fryns, Jean-Pierre, Vermeesch, Joris, Raynaud, Martine, Riess, Olaf, Gribnau, Joost, Katsanis, Nicholas, Devriendt, Koen, Bauer, Peter, Gecz, Jozef, Golzio, Christelle, Gontan, Cristina, and Kalscheuer, Vera M.

Published
2019
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5. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogne, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stephanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Benedicte, Warde, Marie-Therese Abi, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Polsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zoe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikael, Mohammad, Shekeeb S., Armstrong, Ruth, Kalscheuer, Vera M., Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogne, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stephanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Benedicte, Warde, Marie-Therese Abi, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Polsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zoe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikael, Mohammad, Shekeeb S., Armstrong, Ruth, and Kalscheuer, Vera M.

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., Funding Agencies|Fondazione AIRC per la Ricerca sul Cancro [IG 21558]; Italian Ministry for University and Research (MIUR) [PRIN 20174TB8KW]; FWO [1861419N]; Queen Elisabeth Medical Foundation; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]; CPA grant [PG01217]; NHMRC Principal Research Fellowship [GNT1120615]; BICARE, Australia; King Salman Center for Disability Research [RG-2022-010, RG-2022-011]; MRC [MR/T007087/1]; GOSH Charity [VS0122]; Rosetrees Trust [CF2\100018]; NHMRC Investigator Grant [GNT20081]; Projekt DEAL; NIHR GOSH BRC

Published
2023
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7. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., primary, Pusch, Michael, additional, Picollo, Alessandra, additional, Forwood, Caitlin, additional, Nguyen, Matthew H., additional, Suckow, Vanessa, additional, Gibbons, Jessica, additional, Hoff, Alva, additional, Sigfrid, Lisa, additional, Megarbane, Andre, additional, Nizon, Mathilde, additional, Cogné, Benjamin, additional, Beneteau, Claire, additional, Alkuraya, Fowzan S., additional, Chedrawi, Aziza, additional, Hashem, Mais O., additional, Stamberger, Hannah, additional, Weckhuysen, Sarah, additional, Vanlander, Arnaud, additional, Ceulemans, Berten, additional, Rajagopalan, Sulekha, additional, Nunn, Kenneth, additional, Arpin, Stéphanie, additional, Raynaud, Martine, additional, Motter, Constance S., additional, Ward-Melver, Catherine, additional, Janssens, Katrien, additional, Meuwissen, Marije, additional, Beysen, Diane, additional, Dikow, Nicola, additional, Grimmel, Mona, additional, Haack, Tobias B., additional, Clement, Emma, additional, McTague, Amy, additional, Hunt, David, additional, Townshend, Sharron, additional, Ward, Michelle, additional, Richards, Linda J., additional, Simons, Cas, additional, Costain, Gregory, additional, Dupuis, Lucie, additional, Mendoza-Londono, Roberto, additional, Dudding-Byth, Tracy, additional, Boyle, Jackie, additional, Saunders, Carol, additional, Fleming, Emily, additional, El Chehadeh, Salima, additional, Spitz, Marie-Aude, additional, Piton, Amelie, additional, Gerard, Bénédicte, additional, Abi Warde, Marie-Thérèse, additional, Rea, Gillian, additional, McKenna, Caoimhe, additional, Douzgou, Sofia, additional, Banka, Siddharth, additional, Akman, Cigdem, additional, Bain, Jennifer M., additional, Sands, Tristan T., additional, Wilson, Golder N., additional, Silvertooth, Erin J., additional, Miller, Lauren, additional, Lederer, Damien, additional, Sachdev, Rani, additional, Macintosh, Rebecca, additional, Monestier, Olivier, additional, Karadurmus, Deniz, additional, Collins, Felicity, additional, Carter, Melissa, additional, Rohena, Luis, additional, Willemsen, Marjolein H., additional, Ockeloen, Charlotte W., additional, Pfundt, Rolph, additional, Kroft, Sanne D., additional, Field, Michael, additional, Laranjeira, Francisco E. R., additional, Fortuna, Ana M., additional, Soares, Ana R., additional, Michaud, Vincent, additional, Naudion, Sophie, additional, Golla, Sailaja, additional, Weaver, David D., additional, Bird, Lynne M., additional, Friedman, Jennifer, additional, Clowes, Virginia, additional, Joss, Shelagh, additional, Pölsler, Laura, additional, Campeau, Philippe M., additional, Blazo, Maria, additional, Bijlsma, Emilia K., additional, Rosenfeld, Jill A., additional, Beetz, Christian, additional, Powis, Zöe, additional, McWalter, Kirsty, additional, Brandt, Tracy, additional, Torti, Erin, additional, Mathot, Mikaël, additional, Mohammad, Shekeeb S., additional, Armstrong, Ruth, additional, and Kalscheuer, Vera M., additional

Published
2022
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8. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, Kalscheuer, Vera M, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, and Kalscheuer, Vera M

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2022

10. Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, Raman, Corbett, Mark A., Van Bon, Bregje W.M., Gardner, Alison, Woenig, Joshua A., Jolly, Lachlan A., Douglas, Evelyn, Friend, Kathryn, Tan, Chuan, Van Esch, Hilde, Holvoet, Maureen, Raynaud, Martine, Field, Michael, Leffler, Melanie, Budny, Bartłomiej, Wisniewska, Marzena, Badura-Stronka, Magdalena, Latos-Bieleńska, Anna, Batanian, Jacqueline, Rosenfeld, Jill A., Basel-Vanagaite, Lina, Jensen, Corinna, Bienek, Melanie, Froyen, Guy, Ullmann, Reinhard, Hu, Hao, Love, Michael I., Haas, Stefan A., Stankiewicz, Pawel, Cheung, Sau Wai, Baxendale, Anne, Nicholl, Jillian, Thompson, Elizabeth M., Haan, Eric, Kalscheuer, Vera M., and Gecz, Jozef

Published
2015
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11. Erratum: Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders (The American Journal of Human Genetics (2020) 106(3) (356–370), (S0002929720300197), (10.1016/j.ajhg.2020.01.019))

Author

Aref-Eshghi, Erfan, Kerkhof, Jennifer, Pedro, Victor P., France, Groupe D. I., Barat-Houari, Mouna, Ruiz-Pallares, Nathalie, Andrau, Jean-Christophe, Lacombe, Didier, van-Gils, Julien, Fergelot, Patricia, Dubourg, Christéle, Cormier-Daire, Valerie, Rondeau, Sophie, Lecoquierre, François, Saugier-Veber, Pascale, Nicolas, Gaël, Lesca, Gaetan, Chatron, Nicolas, Sanlaville, Damien, Vitobello, Antonio, Faivre, Laurence, Thauvin-Robinet, Christel, Laumonnier, Frederic, Raynaud, Martine, Alders, Mariëlle, Mannens, Marcel, Henneman, Peter, Hennekam, Raoul C., Velasco, Guillaume, Francastel, Claire, Ulveling, Damien, Ciolfi, Andrea, Pizzi, Simone, Tartaglia, Marco, Heide, Solveig, Héron, Delphine, Mignot, Cyril, Keren, Boris, Whalen, Sandra, Afenjar, Alexandra, Bienvenu, Thierry, Campeau, Philippe M., Rousseau, Justine, Levy, Michael A., Brick, Lauren, Kozenko, Mariya, Balci, Tugce B., Siu, Victoria Mok, Stuart, Alan, Kadour, Mike, Masters, Jennifer, Takano, Kyoko, Kleefstra, Tjitske, de Leeuw, Nicole, Field, Michael, Shaw, Marie, Gecz, Jozef, Ainsworth, Peter J., Lin, Hanxin, Rodenhiser, David I., Friez, Michael J., Tedder, Matt, Lee, Jennifer A., DuPont, Barbara R., Stevenson, Roger E., Skinner, Steven A., Schwartz, Charles E., Genevieve, David, Sadikovic, Bekim, Human Genetics, ACS - Pulmonary hypertension & thrombosis, Amsterdam Reproduction & Development (AR&D), Amsterdam Gastroenterology Endocrinology Metabolism, General Paediatrics, and APH - Quality of Care

Abstract

(The American Journal of Human Genetics 106, 356–370; March 5, 2020) In the version of this paper originally published, the underlying cause for Hunter McAlpine syndrome was incorrectly described in Table 1. The relevant description has been changed to read “Chr5q35-qter duplication involving NSD1” in the updated Table 1 reflected here. The authors apologize for this error.

Published
2021

12. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Aref-Eshghi, Erfan, primary, Kerkhof, Jennifer, additional, Pedro, Victor P., additional, France, Groupe DI, additional, Barat-Houari, Mouna, additional, Ruiz-Pallares, Nathalie, additional, Andrau, Jean-Christophe, additional, Lacombe, Didier, additional, Van-Gils, Julien, additional, Fergelot, Patricia, additional, Dubourg, Christéle, additional, Cormier-Daire, Valerie, additional, Rondeau, Sophie, additional, Lecoquierre, François, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, Lesca, Gaetan, additional, Chatron, Nicolas, additional, Sanlaville, Damien, additional, Vitobello, Antonio, additional, Faivre, Laurence, additional, Thauvin-Robinet, Christel, additional, Laumonnier, Frederic, additional, Raynaud, Martine, additional, Alders, Mariëlle, additional, Mannens, Marcel, additional, Henneman, Peter, additional, Hennekam, Raoul C., additional, Velasco, Guillaume, additional, Francastel, Claire, additional, Ulveling, Damien, additional, Ciolfi, Andrea, additional, Pizzi, Simone, additional, Tartaglia, Marco, additional, Heide, Solveig, additional, Héron, Delphine, additional, Mignot, Cyril, additional, Keren, Boris, additional, Whalen, Sandra, additional, Afenjar, Alexandra, additional, Bienvenu, Thierry, additional, Campeau, Philippe M., additional, Rousseau, Justine, additional, Levy, Michael A., additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Balci, Tugce B., additional, Siu, Victoria Mok, additional, Stuart, Alan, additional, Kadour, Mike, additional, Masters, Jennifer, additional, Takano, Kyoko, additional, Kleefstra, Tjitske, additional, de Leeuw, Nicole, additional, Field, Michael, additional, Shaw, Marie, additional, Gecz, Jozef, additional, Ainsworth, Peter J., additional, Lin, Hanxin, additional, Rodenhiser, David I., additional, Friez, Michael J., additional, Tedder, Matt, additional, Lee, Jennifer A., additional, DuPont, Barbara R., additional, Stevenson, Roger E., additional, Skinner, Steven A., additional, Schwartz, Charles E., additional, Genevieve, David, additional, and Sadikovic, Bekim, additional

Published
2021
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13. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author

Halewa, Judith, primary, Marouillat, Sylviane, additional, Dixneuf, Manon, additional, Thépault, Rose‐Anne, additional, Ung, Dévina C., additional, Chatron, Nicolas, additional, Gérard, Bénédicte, additional, Ghoumid, Jamal, additional, Lesca, Gaëtan, additional, Till, Marianne, additional, Smol, Thomas, additional, Couque, Nathalie, additional, Ruaud, Lyse, additional, Chune, Valérie, additional, Grotto, Sarah, additional, Verloes, Alain, additional, Vuillaume, Marie‐Laure, additional, Toutain, Annick, additional, Raynaud, Martine, additional, and Laumonnier, Frédéric, additional

Published
2021
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14. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly

Author

Giannandrea, Maila, Mignogna, Maria Lidia, Sirri, Alessandra, Carrabino, Salvatore, Bianchi, Veronica, D'Elia, Errico, Vecellio, Matteo, Russo, Silvia, Cogliati, Francesca, Larizza, Lidia, Ropers, Hans-Hilger, Kalscheuer, Vera, Tzschach, Andreas, Oehl-Jaschkowitz, Barbara, Skinner, Cindy, Schwartz, Charles E., Gecz, Jozef, Van Esch, Hilde, Raynaud, Martine, Chelly, Jamel, de Brouwer, Arjan P.M., Toniolo, Daniela, and D'Adamo, Patrizia

Subjects
X-linked mental retardation -- Genetic aspects, Guanosine triphosphatase -- Research, Gene mutations -- Research, Protein research, Biological sciences
Abstract

A study reports that mutations in the small GTPase gene RAB39B are responsible for X-linked Human Mental Retardation (HMR) associated with autism, epilepsy, and macrocephaly. Analyses demonstrate that RAB39B, a novel GTPase of the RAB family, is a neuronal-specific protein required for synapse formation and maintenance, and its downregulation due to mutations impairs the development of neurons and human intellectual abilities.

Published
2010

21. ZNF674: a new Kruppel-associated box-containing zinc-finger gene involved in nonsyndromic x-linked mental retardation

Author

Lugtenberg, Dorien, Yntema, Helger G., Banning, Martijn J.G., Oudakker, Astrid R., Firth, Helen V., Willatt, Lionel, Raynaud, Martine, Kleefstra, Tjitske, Fryns, Jean-Pierre, Ropers, Hans-Hilger, Chelly, Jamel, Moraine, Claude, Gecz, Jozef, van Reeuwijk, Jeroen, Nabuurs, Sander B., de Vries, Bert B.A., Hamel, Ben C.J., de Brouwer, Arjan P.M., and van Bokhoven, Hans

Subjects
Biological sciences
Published
2006

22. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males

Author

Van Esch, Hilde, Bauters, Marijke, Ignatius, Jaakko, Jansen, Mieke, Raynaud, Martine, Hollanders, Karen, Lugtenberg, Dorien, Bienvenu, Thierry, Jensen, Lars Riff, Gecz, Jozef, Moraine, Claude, Marynen, Peter, Fryns, Jean-Pierre, and Froyen, Guy

Subjects
Neurologic manifestations of general diseases -- Genetic aspects, Human genetics -- Research, Men -- Health aspects, Men -- Genetic aspects, Biological sciences
Published
2005

24. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family

Author

Laumonnier, Frederic, Bonnet-Brilhault, Frederique, Gomot, Marie, Blanc, Romuald, David, Albert, Moizard, Marie-Pierre, Raynaud, Martine, Ronce, Nathalie, Lamonnier, Eric, Calvas, Patrick, Laudier, Beatrice, Chelly, Jamel, Fryns, Jean-Pierre, Ropers, Hans-Hilger, Hamel, Ben C.J., Andres, Christian, Barthelemy, Catherine, Moraine, Claude, and Briault, Sylvain

Subjects
Biological sciences
Published
2004

25. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. (Report)

Author

Laumonnier, Frederic, Ronce, Nathalie, Hamel, Ben C.J., Thomas, Paul, Lespinasse, James, Raynaud, Martine, Paringaux, Christine, van Bokhoven, Hans, Kalscheuer, Vera, Fryns, Jean-Pierre, Chelly, Jamel, Moraine, Claude, and Briault, Sylvain

Subjects
Mental retardation -- Genetic aspects, Fragile X syndrome -- Research, Genetic disorders -- Research, Familial diseases -- Research, Somatotropin -- Genetic aspects, Somatotropin -- Abnormalities, Stature, Short -- Genetic aspects, Homeobox genes -- Health aspects, Homeobox genes -- Abnormalities, Biological sciences
Published
2002

27. The GRIA3 c.2477G > A Variant Causes an Exaggerated Startle Reflex, Chorea, and Multifocal Myoclonus

Author

Piard, Juliette, primary, Béreau, Matthieu, additional, XiangWei, Wenshu, additional, Wirth, Thomas, additional, Amsallem, Daniel, additional, Buisson, Lauren, additional, Richard, Philippe, additional, Liu, Nana, additional, Xu, Yuchen, additional, Myers, Scott J., additional, Traynelis, Stephen F., additional, Chelly, Jameleddine, additional, Anheim, Mathieu, additional, Raynaud, Martine, additional, Maldergem, Lionel Van, additional, and Yuan, Hongjie, additional

Published
2020
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28. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Aref-Eshghi, Erfan, primary, Kerkhof, Jennifer, additional, Pedro, Victor P., additional, Barat-Houari, Mouna, additional, Ruiz-Pallares, Nathalie, additional, Andrau, Jean-Christophe, additional, Lacombe, Didier, additional, Van-Gils, Julien, additional, Fergelot, Patricia, additional, Dubourg, Christèle, additional, Cormier-Daire, Valerie, additional, Rondeau, Sophie, additional, Lecoquierre, François, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, Lesca, Gaetan, additional, Chatron, Nicolas, additional, Sanlaville, Damien, additional, Vitobello, Antonio, additional, Faivre, Laurence, additional, Thauvin-Robinet, Christel, additional, Laumonnier, Frederic, additional, Raynaud, Martine, additional, Alders, Mariëlle, additional, Mannens, Marcel, additional, Henneman, Peter, additional, Hennekam, Raoul C., additional, Velasco, Guillaume, additional, Francastel, Claire, additional, Ulveling, Damien, additional, Ciolfi, Andrea, additional, Pizzi, Simone, additional, Tartaglia, Marco, additional, Heide, Solveig, additional, Héron, Delphine, additional, Mignot, Cyril, additional, Keren, Boris, additional, Whalen, Sandra, additional, Afenjar, Alexandra, additional, Bienvenu, Thierry, additional, Campeau, Philippe M., additional, Rousseau, Justine, additional, Levy, Michael A., additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Balci, Tugce B., additional, Siu, Victoria Mok, additional, Stuart, Alan, additional, Kadour, Mike, additional, Masters, Jennifer, additional, Takano, Kyoko, additional, Kleefstra, Tjitske, additional, de Leeuw, Nicole, additional, Field, Michael, additional, Shaw, Marie, additional, Gecz, Jozef, additional, Ainsworth, Peter J., additional, Lin, Hanxin, additional, Rodenhiser, David I., additional, Friez, Michael J., additional, Tedder, Matt, additional, Lee, Jennifer A., additional, DuPont, Barbara R., additional, Stevenson, Roger E., additional, Skinner, Steven A., additional, Schwartz, Charles E., additional, Genevieve, David, additional, and Sadikovic, Bekim, additional

Published
2020
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30. Mutation Frequencies of X-linked Mental Retardation Genes in Families from the EuroMRX Consortium

Author

de Brouwer, Arjan P.M., Yntema, Helger G., Kleefstra, Tjitske, Lugtenberg, Dorien, Oudakker, Astrid R., de Vries, Bert B.A., van Bokhoven, Hans, Van Esch, Hilde, Frints, Suzanne G.M., Froyen, Guy, Fryns, Jean-Pierre, Raynaud, Martine, Moizard, Marie-Pierre, Ronce, Nathalie, Bensalem, Anissa, Moraine, Claude, Poirier, Karine, Castelnau, Laetitia, Saillour, Yoann, Bienvenu, Thierry, Beldjord, Chérif, des Portes, Vincent, Chelly, Jamel, Turner, Gillian, Fullston, Tod, Gecz, Jozef, Kuss, Andreas W., Tzschach, Andreas, Jensen, Lars Riff, Lenzner, Steffen, Kalscheuer, Vera M., Ropers, Hans-Hilger, and Hamel, Ben C.J.

Published
2007
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32. P625 : Hydrocéphalie : manifestation rare dans le spectre phénotypique du Syndrome Simpson - Golabi - Behmel, à propos d’un cas

Author

apetrei, andreea, Colson, Cindy, villedieu, florence, Gruchy, Nicolas, Benoist, Guillaume, Raynaud, Martine, Kottler, Marie-Laure, Moizard, Marie-Pierre, Toutain, Annick, Gérard, Marion, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
hydrocéphalie, GPC3, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, ventriculomegalie, ComputingMilieux_MISCELLANEOUS, Syndrome Simpson Golabi Behmel
Abstract

National audience

Published
2018

33. Prenatal diagnosis of fragile X syndrome: Small meiotic recombination events at the FMR1 locus

Author

Bacrot, Séverine, primary, Monnot, Sophie, additional, Haddad, Georges, additional, Barcia, Giulia, additional, Rachid, Myriam, additional, Boisson, Marie, additional, Pasquier, Nathalie, additional, Rondeau, Sophie, additional, Munnich, Arnold, additional, Steffann, Julie, additional, Bonnefont, Jean‐Paul, additional, and Raynaud, Martine, additional

Published
2019
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34. LIMK2-1 is a Hominidae-Specific Isoform of LIMK2 Expressed in Central Nervous System and Associated with Intellectual Disability

Author

Tastet, Julie, primary, Cuberos, Hélène, additional, Vallée, Béatrice, additional, Toutain, Annick, additional, Raynaud, Martine, additional, Marouillat, Sylviane, additional, Thépault, Rose-Anne, additional, Laumonnier, Frédéric, additional, Bonnet-Brilhault, Frédérique, additional, Vourc'h, Patrick, additional, Andres, Christian R., additional, and Bénédetti, Hélène, additional

Published
2019
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35. Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with Intellectual Disability

Author

Tzschach Andreas, Launay Jean-Marie, Delorme Richard, Van Esch Hilde, de Brouwer Arjan, Moreno Sarah, Jamain Stéphane, Dumaine Anne, Poirier Karine, Botros Hany, Pagan Cecile, Kalscheuer Vera, Lacombe Didier, Briault Sylvain, Laumonnier Frédéric, Raynaud Martine, van Bon Bregje W, Willemsen Marjolein H, Leboyer Marion, Chelly Jamel, and Bourgeron Thomas

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls. Methods Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls. Results We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004). Conclusions We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis.

Published
2011
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36. Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Author

Vuillaume, Marie-Laure, primary, Moizard, Marie-Pierre, additional, Rossignol, Sylvie, additional, Cottereau, Edouard, additional, Vonwill, Sandrine, additional, Alessandri, Jean-Luc, additional, Busa, Tiffany, additional, Colin, Estelle, additional, Gérard, Marion, additional, Giuliano, Fabienne, additional, Lambert, Laetitia, additional, Lefevre, Mathilde, additional, Kotecha, Udhaya, additional, Nampoothiri, Sheela, additional, Netchine, Irène, additional, Raynaud, Martine, additional, Brioude, Frédéric, additional, and Toutain, Annick, additional

Published
2018
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37. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., primary, Ozanturk, Aysegul, additional, Rodríguez Criado, Germán, additional, Grasshoff, Ute, additional, de Hoon, Bas, additional, Field, Michael, additional, Manouvrier-Hanu, Sylvie, additional, E. Hickey, Scott, additional, Kammoun, Molka, additional, Gripp, Karen W., additional, Bauer, Claudia, additional, Schroeder, Christopher, additional, Toutain, Annick, additional, Mihalic Mosher, Theresa, additional, Kelly, Benjamin J., additional, White, Peter, additional, Dufke, Andreas, additional, Rentmeester, Eveline, additional, Moon, Sungjin, additional, Koboldt, Daniel C, additional, van Roozendaal, Kees E. P., additional, Hu, Hao, additional, Haas, Stefan A., additional, Ropers, Hans-Hilger, additional, Murray, Lucinda, additional, Haan, Eric, additional, Shaw, Marie, additional, Carroll, Renee, additional, Friend, Kathryn, additional, Liebelt, Jan, additional, Hobson, Lynne, additional, De Rademaeker, Marjan, additional, Geraedts, Joep, additional, Fryns, Jean-Pierre, additional, Vermeesch, Joris, additional, Raynaud, Martine, additional, Riess, Olaf, additional, Gribnau, Joost, additional, Katsanis, Nicholas, additional, Devriendt, Koen, additional, Bauer, Peter, additional, Gecz, Jozef, additional, Golzio, Christelle, additional, Gontan, Cristina, additional, and Kalscheuer, Vera M., additional

Published
2018
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38. Mutation update for theGPC3gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Author

Vuillaume, Marie-Laure, primary, Moizard, Marie-Pierre, additional, Rossignol, Sylvie, additional, Cottereau, Edouard, additional, Vonwill, Sandrine, additional, Alessandri, Jean-Luc, additional, Busa, Tiffany, additional, Colin, Estelle, additional, Gérard, Marion, additional, Giuliano, Fabienne, additional, Lambert, Laetitia, additional, Lefevre, Mathilde, additional, Kotecha, Udhaya, additional, Nampoothiri, Sheela, additional, Netchine, Irène, additional, Raynaud, Martine, additional, Brioude, Frédéric, additional, and Toutain, Annick, additional

Published
2018
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39. Further delineation of theMECP2duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author

Miguet, Marguerite, primary, Faivre, Laurence, additional, Amiel, Jeanne, additional, Nizon, Mathilde, additional, Touraine, Renaud, additional, Prieur, Fabienne, additional, Pasquier, Laurent, additional, Lefebvre, Mathilde, additional, Thevenon, Julien, additional, Dubourg, Christèle, additional, Julia, Sophie, additional, Sarret, Catherine, additional, Remerand, Ganaëlle, additional, Francannet, Christine, additional, Laffargue, Fanny, additional, Boespflug-Tanguy, Odile, additional, David, Albert, additional, Isidor, Bertrand, additional, Vigneron, Jacqueline, additional, Leheup, Bruno, additional, Lambert, Laetitia, additional, Philippe, Christophe, additional, Béri-Dexheimer, Mylène, additional, Cuisset, Jean-Marie, additional, Andrieux, Joris, additional, Plessis, Ghislaine, additional, Toutain, Annick, additional, Guibaud, Laurent, additional, Cormier-Daire, Valérie, additional, Rio, Marlene, additional, Bonnefont, Jean-Paul, additional, Echenne, Bernard, additional, Journel, Hubert, additional, Burglen, Lydie, additional, Chantot-Bastaraud, Sandrine, additional, Bienvenu, Thierry, additional, Baumann, Clarisse, additional, Perrin, Laurence, additional, Drunat, Séverine, additional, Jouk, Pierre-Simon, additional, Dieterich, Klaus, additional, Devillard, Françoise, additional, Lacombe, Didier, additional, Philip, Nicole, additional, Sigaudy, Sabine, additional, Moncla, Anne, additional, Missirian, Chantal, additional, Badens, Catherine, additional, Perreton, Nathalie, additional, Thauvin-Robinet, Christel, additional, AChro-Puce, Réseau, additional, Pedespan, Jean-Michel, additional, Rooryck, Caroline, additional, Goizet, Cyril, additional, Vincent-Delorme, Catherine, additional, Duban-Bedu, Bénédicte, additional, Bahi-Buisson, Nadia, additional, Afenjar, Alexandra, additional, Maincent, Kim, additional, Héron, Delphine, additional, Alessandri, Jean-Luc, additional, Martin-Coignard, Dominique, additional, Lesca, Gaëtan, additional, Rossi, Massimiliano, additional, Raynaud, Martine, additional, Callier, Patrick, additional, Mosca-Boidron, Anne-Laure, additional, Marle, Nathalie, additional, Coutton, Charles, additional, Satre, Véronique, additional, Caignec, Cédric Le, additional, Malan, Valérie, additional, Romana, Serge, additional, Keren, Boris, additional, Tabet, Anne-Claude, additional, Kremer, Valérie, additional, Scheidecker, Sophie, additional, Vigouroux, Adeline, additional, Lackmy-Port-Lis, Marilyn, additional, Sanlaville, Damien, additional, Till, Marianne, additional, Carneiro, Maryline, additional, Gilbert-Dussardier, Brigitte, additional, Willems, Marjolaine, additional, Van Esch, Hilde, additional, Portes, Vincent Des, additional, and El Chehadeh, Salima, additional

Published
2018
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40. Post hoc analysis of plasma amino acid profiles: towards a specific pattern in autism spectrum disorder and intellectual disability

Author

Delaye, Jean-Baptiste, primary, Patin, Franck, additional, Lagrue, Emmanuelle, additional, Le Tilly, Olivier, additional, Bruno, Clement, additional, Vuillaume, Marie-Laure, additional, Raynaud, Martine, additional, Benz-De Bretagne, Isabelle, additional, Laumonnier, Frederic, additional, Vourc’h, Patrick, additional, Andres, Christian, additional, and Blasco, Helene, additional

Published
2018
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42. Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

Author

Bauters, Marijke, Van Esch, Hilde, Friez, Michael J., Fryns, Jean-Pierre, Boespflug-Tanguy, Odile, Zenker, Martin, Marynen, Peter, Vianna-Morgante, Angela M., Rosenberg, Carla, Schwartz, Charles E., Ignatius, Jaakko, Raynaud, Martine, Hollanders, Karen, Govaerts, Karen, Froyen, Guy, Vandenreijt, Kris, Niel, Florence, Blanc, Pierre, and Stevenson, Roger E.

Subjects
Genomics -- Research, DNA replication -- Analysis, DNA -- Structure, Health
Abstract

An extensive fine mapping and breakpoint study of 16 novel microduplications at Xq28 are presented. A two-step mechanism in which Xq28 is first partially inserted near the MECP locus and then followed by breakage-induced replication with strand invasion of the normal sister chromatid is observed, indicating, that the method by which copy number changes happens in areas with a complicated genomic architecture and can produce complex rearrangements.

Published
2008

43. Mortality in myotonic dystrophy patients in the area of prophylactic pacing devices

Author

Marijon, Eloi, Trinquart, Ludovic, Otmani, Akli, Leclercq, Christophe, Fauchier, Laurent, Chevalier, Philippe, Klug, Didier, Defaye, Pascal, Lellouche, Nicolas, Mansourati, Jacques, Deharo, Jean-Claude, Sadoul, Nicolas, Anselme, Frédéric, Maury, Philippe, Davy, Jean-Marc, Extramiana, Fabrice, Hidden-Lucet, Françoise, Probst, Vincent, Bordachar, Pierre, Mansour, Hassan, Chauvin, Michel, Jouven, Xavier, Lavergne, Thomas, Chatellier, Gilles, Le Heuzey, Jean-Yves, Laurent, Valérie, Pellieux, Sybille, Corcia, Philippe, Magro, Pascal, Pierre, Bertrand, Raynaud, Martine, Babuty, Dominique, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de cardiologie, Hôpital Est -Lyon, Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cardiac Stimulation and Rhythmology, CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Risque cardiovasculaire, rigidité-fibrose et hypercoagulabilité (RCV), Université Henri Poincaré - Nancy 1 (UHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de cardiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre SLA, Griset SA, Diehl - Griset, Human Molecular Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie cardiaque et thoracique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, medicine.medical_specialty, Pacemaker, Artificial, Myotonic dystrophy, Sudden death, HV interval, Pacemaker implantation, [SHS]Humanities and Social Sciences, Young Adult, Internal medicine, Medicine, Humans, Myotonic Dystrophy, In patient, ComputingMilieux_MISCELLANEOUS, business.industry, Middle Aged, medicine.disease, Death, Sudden, Cardiac, Respiratory failure, Sustained ventricular tachycardia, Anesthesia, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Atrioventricular block, Follow-Up Studies
Abstract

Objectives Our study purports to determine whether implantation of a prophylactic pacemaker in MD patients with HV interval ≥70ms lowers the risk of sudden death, which may be essentially due to complete atrioventricular block. Background Sudden death occurs more frequently in patients with myotonic dystrophy (MD) than in the control population. Methods From 1994 to 2008, 100 consecutive patients were enrolled, 49 of whom were implanted. Results During an average follow-up of 74±39months, 10 deaths occurred. Nine were due to respiratory failure. Only one sudden death occurred, whereas 46% of patients were considered at risk of sudden death according to the criteria of Groh et al. [5]. The incidence rate of sudden death was only 0.2 per 100patient-years. One patient developed a paroxysmal syncopal sustained ventricular tachycardia. Conclusions The prophylactic implantation of PM in MD patients who are identified as being at risk of sudden death according to Groh's criteria reduced the incidence rate of sudden death. The one sudden death in an implanted MD patient suggests the likelihood that pacemaker implantation did not totally forestall this event. Ventricular arrhythmias may be involved in the sudden deaths in MD patients, in which case the implantation of an implantable cardiac defibrillator could be indicated.

Published
2011

44. Effet des cations sur la déshydratation des boues résiduaires activées

Author

Raynaud, Martine, Vaxelaire, J., Heritier, P., Baudez, J.C., Technologies et systèmes d'information pour les agrosystèmes (UR TSCF), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), LABORATOIRE DE THERMIQUE ENERGETIQUE ET PROCEDES (EA1932) (LATEP), and Université de Pau et des Pays de l'Adour (UPPA)

Subjects
DEWATERING, [SDE]Environmental Sciences, ACTIVATED SLUDGE, FLOC STRUCTURE, CATION
Abstract

International audience; Even after mechanical dewatering, the residual water within activated sludge remains high. Due to its complex structure, this material is usually extremely compressible and known to be difficult to dewater. The ability of sludge to dewater depends on its biological nature, its composition and also the type of treatment it comes from. Indeed, changes in ionic strength and in ionic composition of sludge affect the stability of structural properties of activated sludge and thus the dewatering efficiency. Some authors have highlighted correlations between the ionic strength of sludge and the ability to dewater evaluated by parameters such as CST (Capillary Suction Time) or SRF (Specific Resistance of Filtration) [1-3]. However, those parameters are often limited to fully characterise sludge dewatering. It is usually accepted that the best lab-scale device to investigate sludge behaviour during mechanical dewatering is the Filtration-Compression Cell (FCC). It enables to describe the two successive steps of dewatering: filtration and expression respectively. The purpose of this work was to study the effect of the type and the content of cations on the flocs structure and on the ability of the sludge to be dewatered. In parallel, physicochemical parameters (turbidity, surface charges content, hydrophobicity, EPS content etc.) were analysed to better understand the sludge behaviour during dewatering. Experimental results have shown that the highest the salinity, the slowest the dewatering kinetics but the driest the sludge is. Moreover, the turbidity of the water phase and the surface charges increase with the cations content. These observations can be explained by a change of ionic strength which tends to reduce flocs cohesion and thus lead to flocs disintegration and fine particles release. Due to the presence of fine particles into the bulk water the filter medium and the filter cake tend to clog, which limits the filtrate flowrate namely during the filtration stage. It seems that organic macromolecules such as EPS were also released from the flocs, leading to a decrease of the amount of the water entrapped within flocs which results to an improvement of the sludge dewatering. Moreover, the sludge behaviour during the expression stage seems to depend in part on the change of the flocs structure. The filter cake was more compact when salt was added which tends to limit its compression.

Published
2010

45. IncreasedSTAG2dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, Raman, primary, Corbett, Mark A., additional, Van Bon, Bregje W.M., additional, Gardner, Alison, additional, Woenig, Joshua A., additional, Jolly, Lachlan A., additional, Douglas, Evelyn, additional, Friend, Kathryn, additional, Tan, Chuan, additional, Van Esch, Hilde, additional, Holvoet, Maureen, additional, Raynaud, Martine, additional, Field, Michael, additional, Leffler, Melanie, additional, Budny, Bartłomiej, additional, Wisniewska, Marzena, additional, Badura-Stronka, Magdalena, additional, Latos-Bieleńska, Anna, additional, Batanian, Jacqueline, additional, Rosenfeld, Jill A., additional, Basel-Vanagaite, Lina, additional, Jensen, Corinna, additional, Bienek, Melanie, additional, Froyen, Guy, additional, Ullmann, Reinhard, additional, Hu, Hao, additional, Love, Michael I., additional, Haas, Stefan A., additional, Stankiewicz, Pawel, additional, Cheung, Sau Wai, additional, Baxendale, Anne, additional, Nicholl, Jillian, additional, Thompson, Elizabeth M., additional, Haan, Eric, additional, Kalscheuer, Vera M., additional, and Gecz, Jozef, additional

Published
2015
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46. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Author

Kumar, Raman, primary, Corbett, Mark A., additional, van Bon, Bregje W.M., additional, Woenig, Joshua A., additional, Weir, Lloyd, additional, Douglas, Evelyn, additional, Friend, Kathryn L., additional, Gardner, Alison, additional, Shaw, Marie, additional, Jolly, Lachlan A., additional, Tan, Chuan, additional, Hunter, Matthew F., additional, Hackett, Anna, additional, Field, Michael, additional, Palmer, Elizabeth E., additional, Leffler, Melanie, additional, Rogers, Carolyn, additional, Boyle, Jackie, additional, Bienek, Melanie, additional, Jensen, Corinna, additional, Van Buggenhout, Griet, additional, Van Esch, Hilde, additional, Hoffmann, Katrin, additional, Raynaud, Martine, additional, Zhao, Huiying, additional, Reed, Robin, additional, Hu, Hao, additional, Haas, Stefan A., additional, Haan, Eric, additional, Kalscheuer, Vera M., additional, and Gecz, Jozef, additional

Published
2015
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47. Pathogenetics

Author

Jensen, Lars, Bartenschlager, Heinz, Rujirabanjerd, Sinitdhorn, Tzschach, Andreas, Nümann, Astrid, Janecke, Andreas, Spörle, Ralf, Stricker, Sigmar, Raynaud, Martine, Nelson, John, Hackett, Anna, Fryns, Jean-Pierre, Chelly, Jamel, de Brouwer, Arjan, Hamel, Ben, Gecz, Jozef, Ropers, Hans-Hilger, Kuss, Andreas, Department Human Molecular Genetics [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Department of Animal Breeding and Biotechnology, University of Hohenheim, Department of Molecular Pathology, SA Pathology and Women's and Children's Hospital, Genetische Poliklinik, Klinikum der Universität Heidelberg, Division of Clinical Genetics, Innsbruck Medical University [Austria] (IMU), Department of Developmental Genetics [Berlin], Development and Disease Group [Berlin], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genetic Services of Western Australia, King Edward Memorial Hospital for Women, The GOLD Service, Hunter Genetics, Centre for Human Genetics, University Hospital Leuven, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Adelaide Medical School [Australia], University of Adelaide, The project was funded by The Nationale Genomforschungsnetz (NGFN2), Systematisch-Methodische Plattformen (SMP) RNA project (RS), The Sonderforschungsbereich 577 (SFB577), 5th European Union Framework, ZonMw., Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Innsbruck Medical University [Austria] ( IMU ), Max Planck Institute for Molecular Genetics ( MPIMG ), Development and Disease Group, Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
Genomic disorders and inherited multi-system disorders [IGMD 3], 610 Medical sciences Medicine, Genetics and epigenetic pathways of disease [NCMLS 6], [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Research, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Genetics, Molecular Biology, Pathology and Forensic Medicine
Abstract

Contains fulltext : 89231.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. RESULTS: By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development.We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. CONCLUSIONS: Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.

Published
2010

48. Déshydratation des boues activées en cellule de filtration-compression : écart par rapport à la théorie classique

Author

Raynaud, Martine, Baudez, J.C., Vaxelaire, J., Heritier, P., Technologies et systèmes d'information pour les agrosystèmes (UR TSCF), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), LABORATOIRE DE THERMIQUE ENERGETIQUE ET PROCEDES (EA1932) (LATEP), and Université de Pau et des Pays de l'Adour (UPPA)

Subjects
FILTRATION-COMPRESSION CELL, DEWATERING, FILTRATION, [SDE]Environmental Sciences, ACTIVATED SLUDGE, DARCY'S LAW
Abstract

International audience; Sludge dewatering is classically represented by a (t/V, V) curve with FCC tests, allowing to determine the Specific Resistance of Filtration (SRF) by using Ruth's equation. Many tests in FCC with varying initial sludge concentrations as well as volume suspension dewatered or pressure showed that the SRF was not constant along filtration phase. It implied that filtration theory is not suitable for highly compressible material. In expression phase, sludge dewatering is function of the applied pressure and the historical material. Thus, porosity throughout the cake is dependent of the pressure and some relaxation times.; La déshydratation des boues est classiquement représentée par une courbe dans un diagramme (t/V, V) en utilisant des tests en cellule de filtration-compression, ce qui permet de déterminer la résistance spécifique de filtration à l'aide de l'équation de Ruth. En faisant varier la concentration ou le volume utilisés ou les pressions appliquées, nous montrons que la résistance spécifique de filtration n'est pas constante pendant la phase de filtration. Ce résultat implique que la théorie de la filtraiton n'est pas applicable aux matériaux compressibles tels que les boues. De plus, pendant la phase de compression, la cinétique de déshydratation dépend à la fois de la pression appliquée et de l'histoire du matériau. Aussi, la porosité dépend à la fois de la pression mais aussi des caractéristiques rhéologiques, notamment les temps de relaxation.

Published
2008

49. Blepharophimosis, short humeri, developmental delay and hirschsprung disease: Expanding the phenotypic spectrum ofMED12mutations

Author

Isidor, Bertrand, primary, Lefebvre, Tiphaine, additional, Le Vaillant, Claudine, additional, Caillaud, Gaëlle, additional, Faivre, Laurence, additional, Jossic, Frédéric, additional, Joubert, Madeleine, additional, Winer, Norbert, additional, Le Caignec, Cédric, additional, Borck, Guntram, additional, Pelet, Anna, additional, Amiel, Jeanne, additional, Toutain, Annick, additional, Ronce, Nathalie, additional, Raynaud, Martine, additional, Verloes, Alain, additional, and David, Albert, additional

Published
2014
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