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

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Accès restreint UNIL
Etat: Public
Version: de l'auteur⸱e
Licence: CC BY 4.0
ID Serval
serval:BIB_D9A4B043FC02
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.
Périodique
Journal of medical genetics
Auteur⸱e⸱s
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.
Collaborateur⸱rice⸱s
SYNAPS Study Group
Contributeur⸱rice⸱s
Groppa S., Karashova B.M., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Pérez-Dueñas B., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., Maagdenberg AMJMVD, Verrotti A., Marseglia G., Savasta S., García-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Koutsis G., Mangano S., Scuderi C., Borgione E., Morello G., Stojkovic T., Zollo M., Heimer G., Dauvilliers Y.A., Striano P., Al-Khawaja I., Al-Mutairi F., Sherifa H.
ISSN
1468-6244 (Electronic)
ISSN-L
0022-2593
Statut éditorial
Publié
Date de publication
12/2021
Peer-reviewed
Oui
Volume
58
Numéro
12
Pages
815-831
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Pathogenic variants of GNB5 encoding the β <sub>5</sub> 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.
We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.
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 <sup>-/-</sup> mice were smaller and had a smaller heart than Gnb5 <sup>+/+</sup> and Gnb5 <sup>+/-</sup> , 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 <sup>-/-</sup> mice. In contrast, Gnb5 <sup>-/-</sup> 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.
Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5 <sup>-</sup> <sup>/-</sup> 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.
Mots-clé
GNB5variants, Gnb5-null mouse models, IDDCA, cardiac conduction anomalies, GNB5variants, Gnb5-null mouse models
Pubmed
Web of science
Open Access
Oui
Création de la notice
16/11/2020 14:20
Dernière modification de la notice
23/11/2022 6:50
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