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2. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Author

Dias, Cristina, Estruch, Sara B., Graham, Sarah A., McRae, Jeremy, Sawiak, Stephen J., Hurst, Jane A., Joss, Shelagh K., Holder, Susan E., Morton, Jenny E.V., Turner, Claire, Thevenon, Julien, Mellul, Kelly, Sánchez-Andrade, Gabriela, Ibarra-Soria, Ximena, Deriziotis, Pelagia, Santos, Rui F., Lee, Song-Choon, Faivre, Laurence, Kleefstra, Tjitske, Liu, Pentao, Hurles, Mathew E., Fisher, Simon E., and Logan, Darren W.

Published
2016
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3. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2019
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4. Characterization of the TBR1 interactome:variants associated with neurodevelopmental disorders disrupt novel protein interactions

Author

Sollis, Elliot, den Hoed, Joery, Quevedo, Marti, Estruch, Sara B., Vino, Arianna, Dekkers, Dick H.W., Demmers, Jeroen A.A., Poot, Raymond, Deriziotis, Pelagia, Fisher, Simon E., Sollis, Elliot, den Hoed, Joery, Quevedo, Marti, Estruch, Sara B., Vino, Arianna, Dekkers, Dick H.W., Demmers, Jeroen A.A., Poot, Raymond, Deriziotis, Pelagia, and Fisher, Simon E.

Abstract

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here, we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction.

Published
2023

6. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2019
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7. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, The DDD study, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2018
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17. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Snijders Blok, Lot, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M.A., van Gassen, Koen L.I., Firth, Helen V., Tomkins, Susan, Bodek, Simon, Õunap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoë, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019
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18. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

19. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

20. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, et al, and University of Zurich

Subjects
2716 Genetics (clinical), 1105 Ecology, Evolution, Behavior and Systematics, 1311 Genetics, 10039 Institute of Medical Genetics, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health, 1306 Cancer Research
Published
2017

21. Erratum to: Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders

Author

Estruch, Sara B, primary, Graham, Sarah A, additional, Quevedo, Martí, additional, Vino, Arianna, additional, Dekkers, Dick H W, additional, Deriziotis, Pelagia, additional, Sollis, Elliot, additional, Demmers, Jeroen, additional, Poot, Raymond A, additional, and Fisher, Simon E, additional

Published
2018
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22. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, Andre, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L., I, van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faive, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., Campeau, Philippe M., Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, Andre, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L., I, van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faive, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2018

23. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Genetica Klinische Genetica, Brain, MS Gynaecologische Oncologie, Circulatory Health, Genetica Sectie Genoomdiagnostiek, Child Health, Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, Andre, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L., I, van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faive, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., Campeau, Philippe M., Genetica Klinische Genetica, Brain, MS Gynaecologische Oncologie, Circulatory Health, Genetica Sectie Genoomdiagnostiek, Child Health, Blok, Lot Snijders, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, Andre, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L., I, van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faive, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Published
2018

27. Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Author

Estruch, Sara B., Graham, Sarah A., Chinnappa, Swathi M., Deriziotis, Pelagia, and Fisher, Simon E.

Subjects
Neuroinformatics, Functional genetics, Research, Speech, Transcription factor, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Language, Neuroscience
Abstract

Background Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. Methods We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder. Results We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder. Conclusions Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein. Electronic supplementary material The online version of this article (doi:10.1186/s11689-016-9177-2) contains supplementary material, which is available to authorized users.

Published
2016

30. Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

Author

Sollis, Elliot, primary, Deriziotis, Pelagia, additional, Saitsu, Hirotomo, additional, Miyake, Noriko, additional, Matsumoto, Naomichi, additional, Hoffer, Mariëtte J.V., additional, Ruivenkamp, Claudia A.L., additional, Alders, Mariëlle, additional, Okamoto, Nobuhiko, additional, Bijlsma, Emilia K., additional, Plomp, Astrid S., additional, and Fisher, Simon E., additional

Published
2017
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31. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio, primary, Deriziotis, Pelagia, additional, Steehouwer, Marloes, additional, Gilissen, Christian, additional, Graham, Sarah A., additional, van Dam, Sipko, additional, Hoover-Fong, Julie, additional, Telegrafi, Aida B., additional, Destree, Anne, additional, Smigiel, Robert, additional, Lambie, Lindsday A., additional, Kayserili, Hülya, additional, Altunoglu, Umut, additional, Lapi, Elisabetta, additional, Uzielli, Maria Luisa, additional, Aracena, Mariana, additional, Nur, Banu G., additional, Mihci, Ercan, additional, Moreira, Lilia M. A., additional, Borges Ferreira, Viviane, additional, Horovitz, Dafne D. G., additional, da Rocha, Katia M., additional, Jezela-Stanek, Aleksandra, additional, Brooks, Alice S., additional, Reutter, Heiko, additional, Cohen, Julie S., additional, Fatemi, Ali, additional, Smitka, Martin, additional, Grebe, Theresa A., additional, Di Donato, Nataliya, additional, Deshpande, Charu, additional, Vandersteen, Anthony, additional, Marques Lourenço, Charles, additional, Dufke, Andreas, additional, Rossier, Eva, additional, Andre, Gwenaelle, additional, Baumer, Alessandra, additional, Spencer, Careni, additional, McGaughran, Julie, additional, Franke, Lude, additional, Veltman, Joris A., additional, De Vries, Bert B. A., additional, Schinzel, Albert, additional, Fisher, Simon E., additional, Hoischen, Alexander, additional, and van Bon, Bregje W., additional

Published
2017
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32. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio; https://orcid.org/0000-0001-9413-0348, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko; https://orcid.org/0000-0001-9204-0197, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, et al, Acuna-Hidalgo, Rocio; https://orcid.org/0000-0001-9413-0348, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko; https://orcid.org/0000-0001-9204-0197, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, and et al

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017

33. Identification and functional characterization ofde novo FOXP1variants provides novel insights into the etiology of neurodevelopmental disorder

Author

Sollis, Elliot, primary, Graham, Sarah A., additional, Vino, Arianna, additional, Froehlich, Henning, additional, Vreeburg, Maaike, additional, Dimitropoulou, Danai, additional, Gilissen, Christian, additional, Pfundt, Rolph, additional, Rappold, Gudrun A., additional, Brunner, Han G., additional, Deriziotis, Pelagia, additional, and Fisher, Simon E., additional

Published
2015
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35. De novo TBR1 mutations in sporadic autism disrupt protein functions

Author

Deriziotis, Pelagia, primary, O’Roak, Brian J., additional, Graham, Sarah A., additional, Estruch, Sara B., additional, Dimitropoulou, Danai, additional, Bernier, Raphael A., additional, Gerdts, Jennifer, additional, Shendure, Jay, additional, Eichler, Evan E., additional, and Fisher, Simon E., additional

Published
2014
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38. Erratum: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Author

O'Roak, Brian J, primary, Deriziotis, Pelagia, additional, Lee, Choli, additional, Vives, Laura, additional, Schwartz, Jerrod J, additional, Girirajan, Santhosh, additional, Karakoc, Emre, additional, MacKenzie, Alexandra P, additional, Ng, Sarah B, additional, Baker, Carl, additional, Rieder, Mark J, additional, Nickerson, Deborah A, additional, Bernier, Raphael, additional, Fisher, Simon E, additional, Shendure, Jay, additional, and Eichler, Evan E, additional

Published
2012
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39. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Author

O'Roak, Brian J, primary, Deriziotis, Pelagia, additional, Lee, Choli, additional, Vives, Laura, additional, Schwartz, Jerrod J, additional, Girirajan, Santhosh, additional, Karakoc, Emre, additional, MacKenzie, Alexandra P, additional, Ng, Sarah B, additional, Baker, Carl, additional, Rieder, Mark J, additional, Nickerson, Deborah A, additional, Bernier, Raphael, additional, Fisher, Simon E, additional, Shendure, Jay, additional, and Eichler, Evan E, additional

Published
2011
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41. Insights into the Genetic Foundations of Human Communication.

Author

Fisher, Simon, Graham, Sarah, and Deriziotis, Pelagia

Subjects
COMMUNICATION, GENETIC engineering, DEVELOPMENTAL neurobiology, FOXP2 gene, BRAIN imaging
Abstract

The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior. [ABSTRACT FROM AUTHOR]

Published
2015
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42. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.

Author

O'Roak, Brian J, Deriziotis, Pelagia, Lee, Choli, Vives, Laura, Schwartz, Jerrod J, Girirajan, Santhosh, Karakoc, Emre, MacKenzie, Alexandra P, Ng, Sarah B, Baker, Carl, Rieder, Mark J, Nickerson, Deborah A, Bernier, Raphael, Fisher, Simon E, Shendure, Jay, and Eichler, Evan E

Subjects
*AUTISM spectrum disorders, *EXONS (Genetics)
Abstract

A correction to the article "Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations," by Choli Lee and colleagues that was published in the 2011 issue is presented.

Published
2012
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43. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Lilia Maria de Azevedo Moreira, Joris A. Veltman, Anne Destree, Ercan Mihci, Banu Güzel Nur, Charles Marques Lourenço, Eva Rossier, Simon E. Fisher, Julie S. Cohen, Julie Hoover-Fong, Viviane Borges Ferreira, Mariana Aracena, Aida Telegrafi, Kátia Maria da Rocha, Alexander Hoischen, Julie McGaughran, Hülya Kayserili, Anthony Vandersteen, Lindsday A. Lambie, Bert B.A. de Vries, Sarah A. Graham, Heiko Reutter, Alessandra Baumer, Pelagia Deriziotis, Andreas Dufke, Maria Luisa Giovannucci Uzielli, Robert Smigiel, Theresa A. Grebe, Albert Schinzel, Christian Gilissen, Bregje W.M. van Bon, Careni Spencer, Marloes Steehouwer, Martin Smitka, Alice S. Brooks, Umut Altunoglu, Elisabetta Lapi, Charu Deshpande, Aleksandra Jezela-Stanek, Dafne Dain Gandelman Horovitz, Nataliya Di Donato, Ali Fatemi, Gwenaelle Andre, Lude Franke, Rocio Acuna-Hidalgo, Sipko van Dam, Clinical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah, Dam, Sipko van, Hoover-Fong, Julie, Telegrafi, Aida, Destree, Anne, Smigiel, Robert, Lambie, Lindsday, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G., Mihci, Ercan, Moreira, Lilia M. A., Borges Ferreira, Viviane, Horovitz, Dafne D. G., Rocha, Katia M. da, Jezela-Stanek, Aleksandra, Brooks, Alice S., Reutter, Heiko, Cohen, Julie S., Fatemi, Ali, Smitka, Martin, Grebe, Theresa A., Donato, Nataliya Di, Deshpande, Charu, Vandersteen, Anthony, Lourenço, Charles Marques, Dufke, Andreas, Rossier, Eva, Andre, Gwenaelle, Baumer, Alessandra, Spencer, Careni, McGaughran, Julie, Franke, Lude, Veltman, Joris A., Vries, Bert B. A. de, Schinzel, Albert, Fisher, Simon E., Hoischen, Alexander, Bon, Bregje W. van, School of Medicine, Department of Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Male, Cancer Research, Somatic cell, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gene Identification and Analysis, Gene Expression, medicine.disease_cause, Biochemistry, Germline, Hematologic Cancers and Related Disorders, Craniofacial Abnormalities, Exon, Database and Informatics Methods, Animal Cells, Medicine and Health Sciences, Nuclear protein, Child, Genetics (clinical), ATYPICAL CML, MYELODYSPLASTIC SYNDROME, Connective Tissue Cells, Genetics, Medicine, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], CLONAL HEMATOPOIESIS, Hematology, CHRONIC NEUTROPHILIC LEUKEMIA, Germline Mutation, Phenotype, 3. Good health, Cell Transformation, Neoplastic, Oncology, Connective Tissue, Child, Preschool, Hematologic Neoplasms, Female, Cellular Types, Anatomy, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], Hand Deformities, Congenital, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Research Article, Neuroinformatics, lcsh:QH426-470, Blotting, Western, Nails, Malformed, Protein degradation, Biology, Research and Analysis Methods, Cell Line, PROGRESSIVE BRAIN ATROPHY, 03 medical and health sciences, Germline mutation, Intellectual Disability, Leukemias, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, JUVENILE MYELOMONOCYTIC LEUKEMIA, CHRONIC MYELOID-LEUKEMIA, Protein Interactions, Molecular Biology, Mutation Detection, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Germ-Line Mutation, Cell Proliferation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHILDHOOD-CANCER, Gene Expression Profiling, DISEASE PROGRESSION, Infant, Newborn, Biology and Life Sciences, Cancers and Neoplasms, Proteins, Infant, CSF3R T618I, Cell Biology, Fibroblasts, Chronic neutrophilic leukemia, Chronic myeloid-leukemia, Juvenile myelomonocytic leukemia, Progressive brain atrophy, Myelodysplastic syndrome, Clonal hematopoiesis, Disease progression, Childhood-cancer, Atypical cml, Csf3r T618i, lcsh:Genetics, 030104 developmental biology, Biological Tissue, Biological Databases, HEK293 Cells, Mutation, Mutation Databases, Cancer research, Somatic Mutation, Carcinogenesis, Carrier Proteins
Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients ( including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype., Radboud University Medical Center; Max Planck Society; European Research Council (ERC); VIDI; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Scientific Research

Published
2017

44. Are further genetic factors associated with the risk of developing variant Creutzfeldt–Jakob disease?

Author

Kretzschmar, Hans, Illig, Thomas, Mead, Simon, Poulter, Mark, Uphill, James, Beck, John, Whitfield, Jerome, Webb, Thomas E F, Campbell, Tracy, Adamson, Gary, Deriziotis, Pelagia, Tabrizi, Sarah J, Hummerich, Holger, Verzilli, Claudio, Alpers, Michael P, Whittaker, John C, and Collinge, John

Subjects
*AGE factors in disease, *ALLELES, *CHROMOSOMES, *COMPARATIVE studies, *CREUTZFELDT-Jakob disease, *DNA, *GENETIC polymorphisms, *GENETICS, *RESEARCH methodology, *MEDICAL cooperation, *MEMBRANE proteins, *PRION diseases, *PRIONS, *PUBLIC health surveillance, *QUALITY control, *RESEARCH, *RESEARCH funding, *STATISTICS, *DATA analysis, *EVALUATION research, *SEQUENCE analysis, *GENOTYPES
Abstract

Background: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD).Methods: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.Findings: The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease.Interpretation: The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease. [ABSTRACT FROM AUTHOR]

Published
2009
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45. Functional characterization of rare FOXP2 variants in neurodevelopmental disorder.

Author

Estruch SB, Graham SA, Chinnappa SM, Deriziotis P, and Fisher SE

Abstract

Background: Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain., Methods: We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder., Results: We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder., Conclusions: Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.

Published
2016
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