Dataset Information

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

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.

SUBMITTER: De Nittis P

PROVIDER: S-EPMC8639930 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundLittle is known about body weight status and the association between body weight and common comorbidities in children and adults with Down syndrome (DS), autism spectrum disorder (ASD) and other intellectual and developmental disabilities (IDDs).MethodsData were extracted from the University of Kansas Medical Center's Healthcare Enterprise Repository for Ontological Narration clinical integrated data repository. Measures included demographics (sex, age and race), disability diagnosis, comorbid health conditions, height, weight and body mass index percentiles (BMI%ile; <18 years of age) or BMI (≥18 years of age).ResultsFour hundred and sixty-eight individuals with DS (122 children and 346 adults), 1659 individuals with ASD (1073 children and 585 adults) and 604 individuals with other IDDs (152 children and 452 adults) were identified. A total of 47.0% (DS), 41.9% (ASD) and 33.5% (IDD) of children had overweight/obese (OW/OB), respectively. Children with DS were more likely to have OW/OB compared with children with IDD or ASD [odds ratio (OR) = 1.91, 95% confidence interval (CI): (1.49, 2.46); OR = 1.43, 95% CI: (1.19, 1.72)], respectively. A total of 81.1% (DS), 62.1% (ASD), and 62.4% (IDD) of adults were OW/OB, respectively. Adults with DS were more likely to have OW/OB compared with those with IDD [OR = 2.56, 95% CI: (2.16, 3.02)]. No significant differences were observed by race. In children with ASD, higher OW/OB was associated with significantly higher (compared with non-OW/OB) occurrence of sleep apnoea [OR = 2.94, 95% CI: (2.22, 3.89)], hypothyroidism [OR = 3.14, 95% CI: (2.17, 4.25)] and hypertension [OR = 4.11, 95% CI: (3.05, 5.54)]. In adults with DS, OW/OB was significantly associated with higher risk of sleep apnoea and type 2 diabetes [OR = 2.93, 95% CI: (2.10, 4.09); OR = 1.76, 95% CI: (1.11, 2.79) respectively]. Similarly, in adults with ASD and IDD, OW/OB was significantly associated with higher risk of sleep apnoea [OR = 3.39, 95% CI: (2.37, 4.85) and OR = 6.69, 95% CI: (4.43, 10.10)], type 2 diabetes [OR = 2.25, 95 % CI: (1.68, 3.01) and OR = 5.49, 95% CI: (3.96, 7.61)] and hypertension [OR = 3.55, 95% CI: (2.76, 4.57) and 3.97, 95% CI: (3.17, 4.97)].ConclusionFindings suggest higher rates of OW/OB in individuals with DS compared with ASD and IDD. Given the increased risk of comorbidities associated with the increased risk of OW/OB, identification of effective interventions for this special population of individuals is critical.