J Med. Genet.: auth.: group Reymond

J med. genet. 2020 Nov 10;jmedgenet-2020-107015. doi: 10.1136/jmedgenet-2020-107015. Online ahead of print.

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

Pasquelena De Nittis 1Stephanie Efthymiou 2Alexandre Sarre 3Nicolas Guex 4Jacqueline Chrast 1Audrey Putoux 5Tipu Sultan 6Javeria Raza Alvi 6Zia Ur Rahman 6Faisal Zafar 7Nuzhat Rana 7Fatima Rahman 8Najwa Anwar 8Shazia Maqbool 8Maha S Zaki 9Joseph G Gleeson 10David Murphy 2Hamid Galehdari 11Gholamreza Shariati 12Neda Mazaheri 11Alireza Sedaghat 13SYNAPS Study GroupGaetan Lesca 14Nicolas Chatron 1 14Vincenzo Salpietro 2Marilena Christoforou 2Henry Houlden 2William F Simonds 15Thierry Pedrazzini 16Reza Maroofian 2Alexandre Reymond 17
Collaborators, Affiliations expand


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.

Keywords: GNB5variants; Gnb5-null mouse models; IDDCA; cardiac conduction anomalies.