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1. PIGN encephalopathy: Characterizing the epileptology

Author

Bayat, Allan, primary, de Valles‐Ibáñez, Guillem, additional, Pendziwiat, Manuela, additional, Knaus, Alexej, additional, Alt, Kerstin, additional, Biamino, Elisa, additional, Bley, Annette, additional, Calvert, Sophie, additional, Carney, Patrick, additional, Caro‐Llopis, Alfonso, additional, Ceulemans, Berten, additional, Cousin, Janice, additional, Davis, Suzanne, additional, des Portes, Vincent, additional, Edery, Patrick, additional, England, Eleina, additional, Ferreira, Carlos, additional, Freeman, Jeremy, additional, Gener, Blanca, additional, Gorce, Magali, additional, Heron, Delphine, additional, Hildebrand, Michael S., additional, Jezela‐Stanek, Aleksandra, additional, Jouk, Pierre‐Simon, additional, Keren, Boris, additional, Kloth, Katja, additional, Kluger, Gerhard, additional, Kuhn, Marius, additional, Lemke, Johannes R., additional, Li, Hong, additional, Martinez, Francisco, additional, Maxton, Caroline, additional, Mefford, Heather C., additional, Merla, Giuseppe, additional, Mierzewska, Hanna, additional, Muir, Alison, additional, Monfort, Sandra, additional, Nicolai, Joost, additional, Norman, Jennifer, additional, O'Grady, Gina, additional, Oleksy, Barbara, additional, Orellana, Carmen, additional, Orec, Laura Elena, additional, Peinhardt, Charlotte, additional, Pronicka, Ewa, additional, Rosello, Monica, additional, Santos‐Simarro, Fernando, additional, Schwaibold, Eva Maria Christina, additional, Stegmann, Alexander P. A., additional, Stumpel, Constance T., additional, Szczepanik, Elzbieta, additional, Terczyńska, Iwona, additional, Thevenon, Julien, additional, Tzschach, Andreas, additional, Van Bogaert, Patrick, additional, Vittorini, Roberta, additional, Walsh, Sonja, additional, Weckhuysen, Sarah, additional, Weissman, Barbara, additional, Wolfe, Lynne, additional, Reymond, Alexandre, additional, De Nittis, Pasquelena, additional, Poduri, Annapurna, additional, Olson, Heather, additional, Striano, Pasquale, additional, Lesca, Gaetan, additional, Scheffer, Ingrid E., additional, Møller, Rikke S., additional, and Sadleir, Lynette G., additional

Published
2022
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2. Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of Kabuki Syndrome Patients

Author

Micale, Lucia, Augello, Bartolomeo, Maffeo, Claudia, Selicorni, Angelo, Zucchetti, Federica, Fusco, Carmela, De Nittis, Pasquelena, Pellico, Maria Teresa, Mandriani, Barbara, Fischetto, Rita, Boccone, Loredana, Silengo, Margherita, Biamino, Elisa, Perria, Chiara, Sotgiu, Stefano, Serra, Gigliola, Lapi, Elisabetta, Neri, Marcella, Ferlini, Alessandra, Cavaliere, Maria Luigia, Chiurazzi, Pietro, Monica, Matteo Della, Scarano, Gioacchino, Faravelli, Francesca, Ferrari, Paola, Mazzanti, Laura, Pilotta, Alba, Patricelli, Maria Grazia, Bedeschi, Maria Francesca, Benedicenti, Francesco, Prontera, Paolo, Toschi, Benedetta, Salviati, Leonardo, Melis, Daniela, Di Battista, Eliana, Vancini, Alessandra, Garavelli, Livia, Zelante, Leopoldo, and Merla, Giuseppe

Published
2014
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5. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.

Author

De Nittis, Pasquelena, Efthymiou, Stephanie, Sarre, Alexandre, Guex, Nicolas, Chrast, Jacqueline, Putoux, Audrey, Sultan, Tipu, Alvi, Javeria Raza, ur Rahman, Zia, Zafar, Faisal, Rana, Nuzhat, Rahman, Fatima, Anwar, Najwa, Maqbool, Shazia, Zaki, Maha S., Gleeson, Joseph G., Murphy, David, Galehdari, Hamid, Shariati, Gholamreza, and Mazaheri, Neda

Abstract

Background Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening. [ABSTRACT FROM AUTHOR]

Published
2021
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6. The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals

Author

Giannuzzi, Giuliana, primary, Schmidt, Paul J., additional, Porcu, Eleonora, additional, Willemin, Gilles, additional, Munson, Katherine M., additional, Nuttle, Xander, additional, Earl, Rachel, additional, Chrast, Jacqueline, additional, Hoekzema, Kendra, additional, Risso, Davide, additional, Männik, Katrin, additional, De Nittis, Pasquelena, additional, Baratz, Ethan D., additional, Herault, Yann, additional, Gao, Xiang, additional, Philpott, Caroline C., additional, Bernier, Raphael A., additional, Kutalik, Zoltan, additional, Fleming, Mark D., additional, Eichler, Evan E., additional, and Reymond, Alexandre, additional

Published
2019
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7. Dissecting KMT2D missense mutations in Kabuki syndrome patients

Author

Cocciadiferro, Dario, primary, Augello, Bartolomeo, additional, De Nittis, Pasquelena, additional, Zhang, Jiyuan, additional, Mandriani, Barbara, additional, Malerba, Natascia, additional, Squeo, Gabriella M, additional, Romano, Alessandro, additional, Piccinni, Barbara, additional, Verri, Tiziano, additional, Micale, Lucia, additional, Pasqualucci, Laura, additional, and Merla, Giuseppe, additional

Published
2018
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8. Erratum: GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability (American Journal of Human Genetics (2016) 99(3) (704–710)(S0002929716302294)(10.1016/j.ajhg.2016.06.025))

Author

Lodder, Elisabeth M., De Nittis, Pasquelena, Koopman, Charlotte D., Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A., Boualla, Lamiae, Blom, Nico A., de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J., Eldomery, Mohammad K., Ratbi, Ilham, Wilde, Arthur A.M., de Boer, Teun, Simonds, William F., Neerman-Arbez, Marguerite, Sutton, V. Reid, Kok, Fernando, Lupski, James R., Reymond, Alexandre, Bezzina, Connie R., Bakkers, Jeroen, Merla, Giuseppe, Cardiology, ACS - Heart failure & arrhythmias, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Medical Biology, Human Genetics, Paediatric Cardiology, ANS - Cellular & Molecular Mechanisms, and ANS - Amsterdam Neuroscience

Abstract

(The American Journal of Human Genetics 99, 704–710; September 1, 2016) In the originally published version of this paper, several cells in Table 1 were incorrect. “Lexical production” has now been revised from “nonverbal” to “delayed” for both individuals in family E, and “light RV dilatation” has now been deleted from the “Heart structural abnormalities” row for individual II.1 in family E. Additionally, all instances of “NR” and “NT” (for “not reported” and “not tested”) have been revised to “NA” (for “not available”) throughout. The table is now correct both online and in print. The authors regret these errors and any confusion that might have resulted. Finally, due to technical error, the Supplemental Data file was not complete in the originally published version but now includes all relevant supplemental figures and tables.

Published
2016

9. Correction: GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Lodder, Elisabeth M, De Nittis, Pasquelena, Koopman, Charlotte D, Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A, Boualla, Lamiae, Blom, Nico A, de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J, Eldomery, Mohammad K, Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F, Neerman-Arbez, Marguerite, Sutton, V Reid, Kok, Fernando, Lupski, James R, Reymond, Alexandre, Bezzina, Connie R, Bakkers, Jeroen, and Merla, Giuseppe

Subjects
Published Erratum
Published
2016

10. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Lodder, Elisabeth M., De Nittis, Pasquelena, Koopman, Charlotte D., Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A., Boualla, Lamiae, Blom, Nico A., de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Akdemir, Zeynep Hande Coban, Fish, Richard J., Eldomery, Mohammad K., Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F., Neerman-Arbez, Marguerite, Sutton, V. Reid, Kok, Fernando, Lupski, James R., Reymond, Alexandre, Bezzina, Connie R., Bakkers, Jeroen, Merla, Giuseppe, Lodder, Elisabeth M., De Nittis, Pasquelena, Koopman, Charlotte D., Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A., Boualla, Lamiae, Blom, Nico A., de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Akdemir, Zeynep Hande Coban, Fish, Richard J., Eldomery, Mohammad K., Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F., Neerman-Arbez, Marguerite, Sutton, V. Reid, Kok, Fernando, Lupski, James R., Reymond, Alexandre, Bezzina, Connie R., Bakkers, Jeroen, and Merla, Giuseppe

Published
2016

11. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Lodder, Elisabeth M, De Nittis, Pasquelena, Koopman, Charlotte D, Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A, Boualla, Lamiae, Blom, Nico A, de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J, Eldomery, Mohammad K, Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F, Neerman-Arbez, Marguerite, Sutton, V Reid, Kok, Fernando, Lupski, James R, Reymond, Alexandre, Bezzina, Connie R, Bakkers, Jeroen, Merla, Giuseppe, Lodder, Elisabeth M, De Nittis, Pasquelena, Koopman, Charlotte D, Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A, Boualla, Lamiae, Blom, Nico A, de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J, Eldomery, Mohammad K, Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F, Neerman-Arbez, Marguerite, Sutton, V Reid, Kok, Fernando, Lupski, James R, Reymond, Alexandre, Bezzina, Connie R, Bakkers, Jeroen, and Merla, Giuseppe

Published
2016

12. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Medische Fysiologie, Circulatory Health, Genetica Groep Van Haaften, Lodder, Elisabeth M., De Nittis, Pasquelena, Koopman, Charlotte D., Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A., Boualla, Lamiae, Blom, Nico A., de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Akdemir, Zeynep Hande Coban, Fish, Richard J., Eldomery, Mohammad K., Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F., Neerman-Arbez, Marguerite, Sutton, V. Reid, Kok, Fernando, Lupski, James R., Reymond, Alexandre, Bezzina, Connie R., Bakkers, Jeroen, Merla, Giuseppe, Medische Fysiologie, Circulatory Health, Genetica Groep Van Haaften, Lodder, Elisabeth M., De Nittis, Pasquelena, Koopman, Charlotte D., Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A., Boualla, Lamiae, Blom, Nico A., de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Akdemir, Zeynep Hande Coban, Fish, Richard J., Eldomery, Mohammad K., Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F., Neerman-Arbez, Marguerite, Sutton, V. Reid, Kok, Fernando, Lupski, James R., Reymond, Alexandre, Bezzina, Connie R., Bakkers, Jeroen, and Merla, Giuseppe

Published
2016

13. Correction: GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Medische Fysiologie, Circulatory Health, Genetica Groep Van Haaften, Lodder, Elisabeth M, De Nittis, Pasquelena, Koopman, Charlotte D, Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A, Boualla, Lamiae, Blom, Nico A, de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J, Eldomery, Mohammad K, Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F, Neerman-Arbez, Marguerite, Sutton, V Reid, Kok, Fernando, Lupski, James R, Reymond, Alexandre, Bezzina, Connie R, Bakkers, Jeroen, Merla, Giuseppe, Medische Fysiologie, Circulatory Health, Genetica Groep Van Haaften, Lodder, Elisabeth M, De Nittis, Pasquelena, Koopman, Charlotte D, Wiszniewski, Wojciech, Moura de Souza, Carolina Fischinger, Lahrouchi, Najim, Guex, Nicolas, Napolioni, Valerio, Tessadori, Federico, Beekman, Leander, Nannenberg, Eline A, Boualla, Lamiae, Blom, Nico A, de Graaff, Wim, Kamermans, Maarten, Cocciadiferro, Dario, Malerba, Natascia, Mandriani, Barbara, Coban Akdemir, Zeynep Hande, Fish, Richard J, Eldomery, Mohammad K, Ratbi, Ilham, Wilde, Arthur A M, de Boer, Teun, Simonds, William F, Neerman-Arbez, Marguerite, Sutton, V Reid, Kok, Fernando, Lupski, James R, Reymond, Alexandre, Bezzina, Connie R, Bakkers, Jeroen, and Merla, Giuseppe

Published
2016

14. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Lodder, Elisabeth M., primary, De Nittis, Pasquelena, additional, Koopman, Charlotte D., additional, Wiszniewski, Wojciech, additional, Moura de Souza, Carolina Fischinger, additional, Lahrouchi, Najim, additional, Guex, Nicolas, additional, Napolioni, Valerio, additional, Tessadori, Federico, additional, Beekman, Leander, additional, Nannenberg, Eline A., additional, Boualla, Lamiae, additional, Blom, Nico A., additional, de Graaff, Wim, additional, Kamermans, Maarten, additional, Cocciadiferro, Dario, additional, Malerba, Natascia, additional, Mandriani, Barbara, additional, Akdemir, Zeynep Hande Coban, additional, Fish, Richard J., additional, Eldomery, Mohammad K., additional, Ratbi, Ilham, additional, Wilde, Arthur A.M., additional, de Boer, Teun, additional, Simonds, William F., additional, Neerman-Arbez, Marguerite, additional, Sutton, V. Reid, additional, Kok, Fernando, additional, Lupski, James R., additional, Reymond, Alexandre, additional, Bezzina, Connie R., additional, Bakkers, Jeroen, additional, and Merla, Giuseppe, additional

Published
2016
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15. TRIM8 downregulation in glioma affects cell proliferation and it is associated with patients survival

Author

Micale, Lucia, primary, Fusco, Carmela, additional, Fontana, Andrea, additional, Barbano, Raffaela, additional, Augello, Bartolomeo, additional, De Nittis, Pasquelena, additional, Copetti, Massimiliano, additional, Pellico, Maria Teresa, additional, Mandriani, Barbara, additional, Cocciadiferro, Dario, additional, Parrella, Paola, additional, Fazio, Vito Michele, additional, Dimitri, Lucia Maria Cecilia, additional, D’Angelo, Vincenzo, additional, Novielli, Chiara, additional, Larizza, Lidia, additional, Daga, Antonio, additional, and Merla, Giuseppe, additional

Published
2015
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16. Genomic and Genetic Disorders Biobank

Author

Fusco, Carmela, primary, Micale, Lucia, additional, Pellico, Maria Teresa, additional, D’Addetta, Ester Valentina, additional, Augello, Bartolomeo, additional, Mandriani, Barbara, additional, De Nittis, Pasquelena, additional, Cocciadiferro, Dario, additional, Malerba, Natascia, additional, Sacco, Michele, additional, Zelante, Leopoldo, additional, and Merla, Giuseppe, additional

Published
2015
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17. Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of K abuki Syndrome Patients

Author

Micale, Lucia, primary, Augello, Bartolomeo, additional, Maffeo, Claudia, additional, Selicorni, Angelo, additional, Zucchetti, Federica, additional, Fusco, Carmela, additional, De Nittis, Pasquelena, additional, Pellico, Maria Teresa, additional, Mandriani, Barbara, additional, Fischetto, Rita, additional, Boccone, Loredana, additional, Silengo, Margherita, additional, Biamino, Elisa, additional, Perria, Chiara, additional, Sotgiu, Stefano, additional, Serra, Gigliola, additional, Lapi, Elisabetta, additional, Neri, Marcella, additional, Ferlini, Alessandra, additional, Cavaliere, Maria Luigia, additional, Chiurazzi, Pietro, additional, Monica, Matteo Della, additional, Scarano, Gioacchino, additional, Faravelli, Francesca, additional, Ferrari, Paola, additional, Mazzanti, Laura, additional, Pilotta, Alba, additional, Patricelli, Maria Grazia, additional, Bedeschi, Maria Francesca, additional, Benedicenti, Francesco, additional, Prontera, Paolo, additional, Toschi, Benedetta, additional, Salviati, Leonardo, additional, Melis, Daniela, additional, Di Battista, Eliana, additional, Vancini, Alessandra, additional, Garavelli, Livia, additional, Zelante, Leopoldo, additional, and Merla, Giuseppe, additional

Published
2014
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18. HDAC6 mediates the acetylation of TRIM50

Author

Fusco, Carmela, primary, Micale, Lucia, additional, Augello, Bartolomeo, additional, Mandriani, Barbara, additional, Pellico, Maria Teresa, additional, De Nittis, Pasquelena, additional, Calcagnì, Alessia, additional, Monti, Maria, additional, Cozzolino, Flora, additional, Pucci, Piero, additional, and Merla, Giuseppe, additional

Published
2014
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19. Dissecting KMT2D missense mutations in Kabuki syndrome patients

Author

Tiziano Verri, Barbara Piccinni, Laura Pasqualucci, Pasquelena De Nittis, Natascia Malerba, Jiyuan Zhang, Bartolomeo Augello, Lucia Micale, Giuseppe Merla, Gabriella Maria Squeo, Barbara Mandriani, Dario Cocciadiferro, Alessandro Romano, Cocciadiferro, Dario, Augello, Bartolomeo, De Nittis, Pasquelena, Zhang, Jiyuan, Mandriani, Barbara, Malerba, Natascia, Squeo, Gabriella M., Romano, Alessandro, Piccinni, Barbara, Verri, Tiziano, Micale, Lucia, Pasqualucci, Laura, Merla, Giuseppe, Cocciadiferro, D, Augello, B, De Nittis, P, Zhang, Jy, Mandriani, B, Malerba, N, Squeo, Gm, Romano, A, Piccinni, B, Verri, T, Micale, L, Pasqualucci, L, and Merla, G

Subjects
0301 basic medicine, Models, Molecular, Abnormalities, Multiple, Computer Simulation, DNA-Binding Proteins, Face, Hematologic Diseases, Histone Demethylases, Humans, Mutation, Neoplasm Proteins, Nuclear Proteins, Protein Conformation, Sequence Analysis, Protein, Vestibular Diseases, Mutation, Missense, Methyltransferase, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Genetic, Models, Genetics, medicine, Missense mutation, Allele, Molecular Biology, Genetics (clinical), biology, Protein, Molecular, General Medicine, medicine.disease, 030104 developmental biology, Histone, Histone methyltransferase, biology.protein, Original Article, Abnormalities, Missense, Kabuki syndrome, Multiple, Sequence Analysis, 030217 neurology & neurosurgery
Abstract

Kabuki syndrome is a rare autosomal dominant condition characterized by facial features, various organs malformations, postnatal growth deficiency and intellectual disability. The discovery of frequent germline mutations in the histone methyltransferase KMT2D and the demethylase KDM6A revealed a causative role for histone modifiers in this disease. However, the role of missense mutations has remained unexplored. Here, we expanded the mutation spectrum of KMT2D and KDM6A in KS by identifying 37 new KMT2D sequence variants. Moreover, we functionally dissected 14 KMT2D missense variants, by investigating their impact on the protein enzymatic activity and the binding to members of the WRAD complex. We demonstrate impaired H3K4 methyltransferase activity in 9 of the 14 mutant alleles and show that this reduced activity is due in part to disruption of protein complex formation. These findings have relevant implications for diagnostic and counseling purposes in this disease.

Published
2018

20. Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of Kabuki Syndrome Patients

Author

Gioacchino Scarano, Alessandra Ferlini, Gigliola Serra, Maria Teresa Pellico, Bartolomeo Augello, Loredana Boccone, Lucia Micale, Federica Zucchetti, Angelo Selicorni, Livia Garavelli, Leopoldo Zelante, Elisabetta Lapi, Alessandra Vancini, Giuseppe Merla, Alba Pilotta, Laura Mazzanti, Leonardo Salviati, Carmela Fusco, Francesca Faravelli, Maria Grazia Patricelli, Daniela Melis, Stefano Sotgiu, Maria Luigia Cavaliere, Matteo Della Monica, Claudia Maffeo, Chiara Perria, Francesco Benedicenti, Paolo Prontera, Eliana Di Battista, Maria Francesca Bedeschi, Benedetta Toschi, Pasquelena De Nittis, Elisa Biamino, Rita Fischetto, Pietro Chiurazzi, Paola Ferrari, Barbara Mandriani, Marcella Neri, Margherita Silengo, Micale, Lucia, Augello, Bartolomeo, Maffeo, Claudia, Selicorni, Angelo, Zucchetti, Federica, Fusco, Carmela, De Nittis, Pasquelena, Pellico, Maria Teresa, Mandriani, Barbara, Fischetto, Rita, Boccone, Loredana, Silengo, Margherita, Biamino, Elisa, Perria, Chiara, Sotgiu, Stefano, Serra, Gigliola, Lapi, Elisabetta, Neri, Marcella, Ferlini, Alessandra, Cavaliere, Maria Luigia, Chiurazzi, Pietro, Monica, Matteo Della, Scarano, Gioacchino, Faravelli, Francesca, Ferrari, Paola, Mazzanti, Laura, Pilotta, Alba, Patricelli, Maria Grazia, Bedeschi, Maria Francesca, Benedicenti, Francesco, Prontera, Paolo, Toschi, Benedetta, Salviati, Leonardo, Melis, Daniela, Di Battista, Eliana, Vancini, Alessandra, Garavelli, Livia, Zelante, Leopoldo, and Merla, Giuseppe

Subjects
Transcription, Genetic, PREDICTION, Nonsense-mediated decay, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Settore MED/03 - GENETICA MEDICA, Cohort Studies, KDM6A, KMT2D, Kabuki syndrome, haploinsufficiency, readthrough, readthrough KeyWords Plus:HISTONE H3, DNA sequencing, Gentamicin, Vestibular Disease, MENTAL-RETARDATION, MLL2, MUTATIONS, GENES, SPECTRUM, DEMETHYLASE, GROWTH, Research Articles, Genetics (clinical), Nuclear Protein, Genetics, Histone Demethylases, Mutation, Translational readthrough, MLL2 gene, Nuclear Proteins, Homeodomain Protein, KDM6A gene, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Codon, Nonsense, RNA Splice Site, Haploinsufficiency, KDM6A, KMT2D, Kabuki syndrome, haploinsufficiency, readthrough, Human, DNA-Binding Protein, Nonsense mutation, Genetic Association Studie, Biology, MED/39 Neuropsichiatria infantile, Cell Line, DNA Mutational Analysi, Neoplasm Protein, Genetic, medicine, Humans, Abnormalities, Multiple, Multiplex ligation-dependent probe amplification, Gene, Genetic Association Studies, Homeodomain Proteins, Sequence Analysis, DNA, Hematologic Disease, medicine.disease, Hematologic Diseases, Nonsense Mediated mRNA Decay, Gene Expression Regulation, Face, Histone Demethylase, RNA Splice Sites, Gentamicins, Cohort Studie
Abstract

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients’ lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.

Published
2014

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