Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome
| Autor: | De Nittis P., Efthymiou S., Sarre A., Guex N., Chrast J., Putoux A., Sultan T., Raza Alvi J., Ur Rahman Z., Zafar F., Rana N., Rahman F., Anwar N., Maqbool S., Zaki M. S., Gleeson J. G., Murphy D., Galehdari H., Shariati G., Mazaheri N., Sedaghat A., Lesca G., Chatron N., Salpietro V., Christoforou M., Houlden H., Simonds W. F., Pedrazzini T., Maroofian R., Reymond A., SYNAPS STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Salvatore Mangano, Carmela Scuderi, Giovanna Morello, Tanya Stojkovic, Massimo Zollo, Gali Heimer, Yves A. Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa. |
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| Přispěvatelé: | University of Lausanne (UNIL), University College of London [London] (UCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Children's Hospital [Lahore], Institute of Child Health [Lahore], Children's Hospital [Multan], Institute of Child Health [Multan], National Research Centre - NRC (EGYPT), Howard Hughes Medical Institute (HHMI), Shahid Chamran University of Ahvaz (SCU), Ahvaz Jundishapur University of Medical Sciences (AJUMS), National Institutes of Health [Bethesda] (NIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Herrada, Anthony, P., De Nitti, S., Efthymiou, A., Sarre, N., Guex, J., Chrast, A., Putoux, T., Sultan, J., Raza Alvi, Z., Ur Rahman, F., Zafar, N., Rana, F., Rahman, N., Anwar, S., Maqbool, M. S., Zaki, J. G., Gleeson, D., Murphy, H., Galehdari, G., Shariati, N., Mazaheri, A., Sedaghat, G., Lesca, N., Chatron, V., Salpietro, M., Christoforou, H., Houlden, W. F., Simond, T., Pedrazzini, R., Maroofian, A., Reymond, STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Synap, Marinova Karashova, Blagovesta, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez-Dueñas, Belen, S Goraya, Jatinder, Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda-Marfa, Mercede, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M. J. M., Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García-Silva, Mayte, Macaya Ruiz, Alfon, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Monteagudo Sanchez, Benigno, Boles, Richard, Papacostas, Savva, Vikelis, Michail, Zamba Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Noureen Rana, Nuzhat, Atawneh, Osama, Koutsis, George, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Zollo, Massimo, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al-Khawaja, Issam, Al-Mutairi, Fuad, Sherifa., Hamed |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Developmental Disabilities Batecs cardíacs 0302 clinical medicine Neurodevelopmental disorder Heart Rate Medicine Child Genetics (clinical) Mice Knockout Gnb5-null mouse models GTP-Binding Protein beta Subunits Cardiac muscle Heart Syndrome IDDCA Functional Genomics Pedigree [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system cardiac conduction anomalies Gnb5 -null mouse models GNB5 variants medicine.anatomical_structure Child Preschool [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Female medicine.symptom Signal Transduction Bradycardia Cardiac function curve Gnb5 -null mouse model medicine.medical_specialty Adolescent [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Contractility Young Adult Brain damage 03 medical and health sciences [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system GNB5variants [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Internal medicine Exome Sequencing Heart rate Genetics Animals Humans business.industry Gene Expression Profiling Heart beat Proteins Cardiac arrhythmia Arrhythmias Cardiac GNB5 variant medicine.disease Mice Inbred C57BL Autonomic nervous system 030104 developmental biology Endocrinology [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Mutation Lesions cerebrals cardiac conduction anomalie business Proteïnes 030217 neurology & neurosurgery |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Journal of Medical Genetics Journal of Medical Genetics, BMJ Publishing Group, In press, ⟨10.1136/jmedgenet-2020-107015⟩ |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | BackgroundPathogenic 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.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe 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.ConclusionsOur 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. |
| Databáze: | OpenAIRE |
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