DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for RAB23-related Carpenter syndrome — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleRAB23-related Carpenter syndrome maps to a 3-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 rab23-related carpenter 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
RAB23, member RAS oncogene family (RAB23) — RAB23 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 gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8YL3 · 1.2 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
RAB23-related Carpenter syndrome is an autosomal recessive disorder caused by mutations in the RAB23 gene, which encodes a small GTPase involved in SHH signalling and membrane trafficking. In 15 out of 16 families reported by 2011, the disease was caused by homozygosity for truncating mutations, with only a single missense mutation identified in a compound heterozygote at that time. A further 8 independent families comprising 10 affected individuals were later described, including the first homozygous missense mutation, in-frame deletion, and splice-site mutation. By 2022, 100 patients had been reported with 14 mutations in the RAB23 gene. A 2012 report of two children from a consanguineous Emirati family identified a homozygous splice-site mutation (c.482-1G>A) that caused an eight nucleotide deletion, frameshift, and premature termination at position 161 (p.V161fsX3), leading to loss of the C-terminally prenylatable cysteine residue. Experimental evidence from 2011 showed that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in pathogenesis.
Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. Other typical features include acrocephaly, syndactyly, brachydactyly, preaxial polydactyly of the toes, typical facial appearance, obesity, and congenital heart disease. High birth weight was not evident in one group of patients, but further evidence for laterality defects was reported. No genotype-phenotype correlations are apparent. A 2011 case report noted an unusual association of Carpenter syndrome with chronic kidney disease, but this was a single observation. The estimated prevalence is one in a million births.
A 2024 study investigated the functional interactions of CPLANE proteins and Rab23 in neural tube closure, using knockdown and point mutants of Rab23. The underlying mechanism linking Rab23 function to Carpenter syndrome remained unclear. The distinctive manifestation of chronic kidney disease in one case added a novel dimension, but further research was warranted to unravel the genetic and molecular pathways. What is still missing is a clear mechanistic understanding of how RAB23 mutations produce the full clinical spectrum, larger patient cohorts to establish any genotype-phenotype correlations, and systematic investigation of whether the chronic kidney disease association is coincidental or syndromic.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2011 · 44 citations · open access
Carpenter syndrome: extended <i>RAB23</i> mutation spectrum and analysis of nonsense‐mediated mRNA decay
AbstractCarpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.
Scholars Journal of Medical Case Reports · 2022 · 1 citations · open access
Carpenter Syndrome: Report of Two Cases
AbstractCarpenter syndrome (MIM 201000) is a rare autosomal recessive disorder characterized by combination of acrocephaly, syndactyly and brachydactyly in the hands as well as syndactyly and preaxial polydactyly of the toes. Other variable features can be present. 100 patients have been reported until now, with 14 mutations in the conserved sequence encoding the ras-like in rat brain 23 (RAB23) gen identified. We report here two Moroccan cases with a typical clinical picture of carpenter syndrome.
INDIGO (University of Illinois at Chicago) · 2012 · 0 citations · open access
Supplementary Material for: A Novel Aberrant Splice Site Mutation in <b><i>RAB23</i></b> Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family
AbstractCarpenter syndrome is caused by mutations in the <i>RAB23</i> gene that encodes a small GTPase of the Rab subfamily of proteins. Rab proteins are known to be involved in the regulation of cellular trafficking and signal transduction. Currently, only few mutations in <i>RAB23 </i>have been reported in patients with Carpenter syndrome. In this paper, we report the clinical features, molecular and functional analysis of 2 children from an Emirati consanguineous family with this syndrome. The affected children exhibit the typical features including craniosynostosis, typical facial appearance, polysyndactyly, and obesity. Molecular analysis of the <i>RAB23</i> gene revealed a homozygous mutation affecting the first nucleotide of the acceptor splice site of exon 5 (c.482-1G>A). This mutation affects the authentic mRNA splicing and activates a cryptic acceptor site within exon 5. Thus, the erroneous splicing results in an eight nucleotide deletion, followed by a frameshift and premature termination codon at position 161 (p.V161fsX3). Due to the loss of the C-terminally prenylatable cysteine residue, the truncated protein will probably fail to associate with the target cellular membranes due to the absence of the necessary lipid modification. The p.V161fsX3 extends the spectrum of <i>RAB23</i> mutations and points to the crucial role of prenylation in the pathogenesis of Carpenter syndrome within this family.
AbstractCarpenter syndrome, characterized by RAB23 mutations, is a rare autosomal recessive disorder distinguished by unique features such as craniofacial anomalies, congenital heart disease, brachydactyly, and obesity. This syndrome's rarity, with an estimated prevalence of one in a million births, poses diagnostic challenges due to its diverse clinical spectrum. Notably, this case report highlights an unusual association of Carpenter syndrome with chronic kidney disease (CKD), underscoring the need for further exploration into the syndromic interplay and shared genetic pathways. The distinctive manifestation of CKD in the context of Carpenter syndrome adds a novel dimension, emphasizing the importance of timely diagnosis and comprehensive care. Further research is warranted to unravel the intricate genetic and molecular pathways underlying the syndrome's diverse manifestations, shedding light on potential shared mechanisms and paving the way for targeted interventions and enhanced patient care.
Texas Digital Library (University of Texas) · 2024 · 0 citations · open access
Probing the functional interactions of CPLANE proteins and Rab23 in neural tube closure
AbstractCilia are microtubule-based organelles essential for development and homeostasis. Proper functionality of these organelles relies on stringent regulation of protein complexes and signaling events. One such important protein is Rab23, a GTPase involved in SHH signaling and membrane trafficking (Hor, Lo, Cham, Leong, & Goh, 2021; Jenkins et al., 2007) Mutations in this gene are linked to Carpenter Syndrome, a disorder characterized by typical ciliopathic signs (Hasan, Koskenranta, Alakurtti, Takatalo, & Rice, 2023; Jenkins et al., 2007). Despite its known role in congenital anomalies and cilia, the underlying mechanism that links this GTPase’s function to carpenter syndrome remains unclear. This study aims to investigate this mechanism using knockdown and point mutants of Rab23.
Supplementary Material for: A Novel Aberrant Splice Site Mutation in <b><i>RAB23</i></b> Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family
AbstractCarpenter syndrome is caused by mutations in the <i>RAB23</i> gene that encodes a small GTPase of the Rab subfamily of proteins. Rab proteins are known to be involved in the regulation of cellular trafficking and signal transduction. Currently, only few mutations in <i>RAB23 </i>have been reported in patients with Carpenter syndrome. In this paper, we report the clinical features, molecular and functional analysis of 2 children from an Emirati consanguineous family with this syndrome. The affected children exhibit the typical features including craniosynostosis, typical facial appearance, polysyndactyly, and obesity. Molecular analysis of the <i>RAB23</i> gene revealed a homozygous mutation affecting the first nucleotide of the acceptor splice site of exon 5 (c.482-1G>A). This mutation affects the authentic mRNA splicing and activates a cryptic acceptor site within exon 5. Thus, the erroneous splicing results in an eight nucleotide deletion, followed by a frameshift and premature termination codon at position 161 (p.V161fsX3). Due to the loss of the C-terminally prenylatable cysteine residue, the truncated protein will probably fail to associate with the target cellular membranes due to the absence of the necessary lipid modification. The p.V161fsX3 extends the spectrum of <i>RAB23</i> mutations and points to the crucial role of prenylation in the pathogenesis of Carpenter syndrome within this family.
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.
