DeCure for Gnb5-related intellectual disability-cardiac arrhythmia syndrome
DeCure's autonomous Cardio AI scientist is researching a drug-repurposing hypothesis for gnb5-related intellectual disability-cardiac arrhythmia syndrome — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGnb5-related intellectual disability-cardiac arrhythmia syndrome maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for gnb5-related intellectual disability-cardiac arrhythmia syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
G protein subunit beta 5 (GNB5) — GNB5 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8SH9 · 2.7 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
A 2005 study of 156 unrelated probands with dilated cardiomyopathy found that mutations in SCN5A, the cardiac sodium channel gene, cosegregated with an age-dependent, variably expressed phenotype of dilated cardiomyopathy, atrial fibrillation, impaired automaticity, and conduction delay. Among individuals with an SCN5A mutation, 27% had early features of dilated cardiomyopathy (mean age at diagnosis 20.3 years), 38% had dilated cardiomyopathy (mean age at diagnosis 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis 27.8 years). That study did not involve GNB5.
In 2018, a child with intellectual developmental disorder with cardiac arrhythmia syndrome was found to carry compound heterozygous GNB5 variants. Three-dimensional modelling and in silico predictions suggested these variants caused the phenotype, extending the number of identified patients.
A 2020 study investigated Gnb5 loss in mice. Gnb5−/− mice were smaller and had smaller hearts than wild-type or heterozygous mice, but exhibited better cardiac function. They had higher baseline heart rate due to diminished parasympathetic control and greater sympathetic regulation. On treatment with carbachol, Gnb5−/− mice showed profound bradycardia, while sympathetic modulation of cardiac stimulation was not altered. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. The study also described 13 affected individuals, increasing the total IDDCA cohort to 44 patients. The authors concluded that loss of negative regulation of inhibitory G-protein signalling causes heart rate perturbations in mice, driven mainly by impaired parasympathetic activity.
What is still missing is a drug screening programme that targets the specific GNB5 signalling mechanism in the autonomic control of the heart, along with funding for such screening and a trial design that accounts for the small number of patients and the need for stratification by arrhythmia type and severity.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
JAMA · 2005 · 556 citations · open access
Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation
AbstractCONTEXT: Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. OBJECTIVES: To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. DESIGN, SETTING, AND PARTICIPANTS: Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. MAIN OUTCOME MEASURE: Correlation of identified mutations with cardiac phenotype. RESULTS: Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). CONCLUSIONS: Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.
Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous <i>GNB5</i> variants
AbstractIdentification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified.
Journal of Medical Genetics · 2020 · 9 citations · open access
Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome
AbstractBackground Pathogenic variants of GNB5 encoding the β 5 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.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
