Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome. Issue 12 (10th November 2020)

• Record Type: Journal Article
• Authors: De Nittis, Pasquelena; Efthymiou, Stephanie; Sarre, Alexandre; Guex, Nicolas; Chrast, Jacqueline; Putoux, Audrey; Sultan, Tipu; Raza Alvi, Javeria; 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; Mazaheri, Neda; Sedaghat, Alireza; Lesca, Gaetan; Chatron, Nicolas; Salpietro, Vincenzo; Christoforou, Marilena; Houlden, Henry; Simonds, William F; Pedrazzini, Thierry; Maroofian, Reza; Reymond, Alexandre
• Other Names: author non-byline.; Groppa Stanislav author non-byline.; Karashova Blagovesta Marinova author non-byline.; Nachbauer Wolfgang author non-byline.; Boesch Sylvia author non-byline.; Arning Larissa author non-byline.; Timmann Dagmar author non-byline.; Cormand Bru author non-byline.; Pérez-Dueñas Belen author non-byline.; Goraya Jatinder S author non-byline.; Sultan Tipu author non-byline.; Mine Jun author non-byline.; Avdjieva Daniela author non-byline.; Kathom Hadil author non-byline.; Tincheva Radka author non-byline.; Banu Selina author non-byline.; Pineda-Marfa Mercedes author non-byline.; Veggiotti Pierangelo author non-byline.; Ferrari Michel D author non-byline.; Maagdenberg Arn M J M van den author non-byline.; Verrotti Alberto author non-byline.; Marseglia Giangluigi author non-byline.; Savasta Salvatore author non-byline.; García-Silva Mayte author non-byline.; Ruiz Alfons Macaya author non-byline.; Garavaglia Barbara author non-byline.; Borgione Eugenia author non-byline.; Portaro Simona author non-byline.; Sanchez Benigno Monteagudo author non-byline.; Boles Richard author non-byline.; Papacostas Savvas author non-byline.; Vikelis Michail author non-byline.; Papanicolaou Eleni Zamba author non-byline.; Dardiotis Efthymios author non-byline.; Maqbool Shazia author non-byline.; Ibrahim Shahnaz author non-byline.; Kirmani Salman author non-byline.; Rana Nuzhat Noureen author non-byline.; Atawneh Osama author non-byline.; Koutsis George author non-byline.; Mangano Salvatore author non-byline.; Scuderi Carmela author non-byline.; Borgione Eugenia author non-byline.; Morello Giovanna author non-byline.; Stojkovic Tanya author non-byline.; Zollo Massimo author non-byline.; Heimer Gali author non-byline.; Dauvilliers Yves A author non-byline.; Striano Pasquale author non-byline.; Al-Khawaja Issam author non-byline.; Al-Mutairi Fuad author non-byline.; Sherifa Hamed author non-byline.;
• Is Part Of: Journal of medical genetics. Volume 58:Issue 12(2021)
• Page Start: 815
• Page End: 831
• Publication Date: 2020-11-10
• Subjects: GNB5variants -- Gnb5-null mouse models -- IDDCA -- cardiac conduction anomalies; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2020-107015
• Languages: English
• ISSNs: 1468-6244

Abstract

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.