De Nittis, P;
Efthymiou, S;
Sarre, A;
Guex, N;
Chrast, J;
Putoux, A;
Sultan, T;
Raza Alvi, J;
Ur Rahman, Z;
Zafar, F;
et al.
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, MS; Gleeson, JG; Murphy, D; Galehdari, H; Shariati, G; Mazaheri, N; Sedaghat, A; SYNAPS Study Group; Lesca, G; Chatron, N; Salpietro, V; Christoforou, M; Houlden, H; Simonds, WF; Pedrazzini, T; Maroofian, R; Reymond, A
(2021)
Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.
J Med Genet, 58 (12).
pp. 815-831.
ISSN 1468-6244
https://doi.org/10.1136/jmedgenet-2020-107015
SGUL Authors: Maroofian, Reza
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.
Item Type: |
Article
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Additional Information: |
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
Keywords: |
GNB5variants, Gnb5-null mouse models, IDDCA, cardiac conduction anomalies, SYNAPS Study Group, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
J Med Genet |
ISSN: |
1468-6244 |
Language: |
eng |
Dates: |
Date | Event |
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22 November 2021 | Published | 10 November 2020 | Published Online | 4 September 2020 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
33172956 |
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Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112612 |
Publisher's version: |
https://doi.org/10.1136/jmedgenet-2020-107015 |
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