Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome
| العنوان: | Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome |
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| المؤلفون: | 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. |
| المساهمون: | 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 |
| المصدر: | 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⟩ |
| بيانات النشر: | BMJ, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1468-6244 0022-2593 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0c9ebc9c3b81e32161c102409b0091dfTest https://doi.org/10.1136/jmedgenet-2020-107015Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0c9ebc9c3b81e32161c102409b0091df |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14686244 00222593 |
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