DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for DOORS 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 moduleDOORS 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 doors 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
ATPase H+ transporting V1 subunit B2 (ATP6V1B2) — ATP6V1B2 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 6WLZ · 2.9 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
DOORS syndrome is caused by mutations in either TBC1D24 or ATP6V1B2, and a 2024 study identified ATP6V1C1 as a new gene associated with a neurodevelopmental phenotype resembling DOORS syndrome. The same 2024 work, using cell models, found that dominant ATP6V1B2 and ATP6V1C1 amino acid substitutions result in a gain-of-function mechanism that upregulates V-ATPase function, driving increased lysosomal acidification. These variants disrupted lysosomal morphology, localisation, and function, leading to defective autophagic flux and accumulation of lysosomal substrates, and also affected cilium biogenesis. The authors classify DOORS, Zimmermann-Laband syndrome, and dominant deafness-onychodystrophy syndrome as lysosomal disorders and describe a phenotypic continuum among them.
A 2020 case report from Indonesia described a 27-day-old girl with recurrent seizures, absence of all finger- and toenails since birth, left eye strabismus, and a single transverse palmar crease on both hands. X-rays showed absence of the distal phalanx of fingers II–V and toes I–V. Brainstem-evoked response audiometry revealed profound bilateral sensorineural deafness, and echocardiography diagnosed pentalogy of Fallot. This was the first report associating pentalogy of Fallot and a single transverse palmar crease with DOORS syndrome.
A separate 2020 neuropathological report examined a 72-year-old Caucasian male with a presumable de novo p.Arg506X mutation in ATP6V1B2 who presented all typical cardinal signs of DOORS syndrome plus behavioural alterations, pyramidal signs, and Parkinsonism. Detailed neuropathology revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. The authors suggest this tauopathy may be a consequence of lysosomal or mitochondrial dysfunction, similar to that seen in Niemann–Pick type C disease.
No treatment or intervention was tested in any of these studies. What remains missing is any clinical trial, any preclinical drug testing in animal models or patient-derived cells, and any systematic effort to stratify patients by genotype (TBC1D24 versus ATP6V1B2 versus ATP6V1C1) or by specific variant type. Funding for natural history studies and for repurposing screens against the lysosomal acidification gain-of-function mechanism has not been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Neurology · 2020 · 14 citations · open access
Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene
AbstractDOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures) syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann–Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.
Human Genetics and Genomics Advances · 2024 · 8 citations · open access
Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function
Abstract-ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome. Here, we report on an individual with features fitting DOORS syndrome caused by dysregulated ATP6V1C1 function, expand the clinical features associated with ATP6V1B2 pathogenic variants, and provide evidence that these ATP6V1C1/ATP6V1B2 amino acid substitutions result in a gain-of-function mechanism upregulating V-ATPase function that drives increased lysosomal acidification. We demonstrate a disruptive effect of these ATP6V1B2/ATP6V1C1 variants on lysosomal morphology, localization, and function, resulting in a defective autophagic flux and accumulation of lysosomal substrates. We also show that the upregulated V-ATPase function affects cilium biogenesis, further documenting pleiotropy. This work identifies ATP6V1C1 as a new gene associated with a neurodevelopmental phenotype resembling DOORS syndrome, documents the occurrence of a phenotypic continuum between ZLS, and DDOD and DOORS syndromes, and classify these conditions as lysosomal disorders.
European Journal of Dermatology · 2020 · 3 citations · open access
Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature
AbstractBACKGROUND: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures; MIM 220500) is a rare multisystem genetic disorder, mainly characterized by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficit, and seizures. The disease is caused by homozygous or compound heterozygous mutation in the TBC1 domain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome 16p13. OBJECTIVES: We report the first case of DOORS syndrome from Indonesia. MATERIALS AND METHODS: A review of the literature was conducted and cases compared. RESULTS: A 27-day-old baby girl was brought to us with a history of recurrent seizures and absence of all finger- and toenails since birth. In addition, physical examination revealed left eye strabismus and a single transverse palmar crease on both hands. X-rays of the hands and feet showed absence of the distal phalanx of her right and left fingers II-V and the distal phalanx of her right and left toes I-V, respectively. Brainstem-evoked response audiometry test revealed profound bilateral sensorineural deafness. Pentalogy of Fallot was diagnosed by echocardiography, while an abnormal diffuse epileptiform pattern was found on electroencephalography. CONCLUSION: This is the first report of an association between pentalogy of Fallot and single transverse palmar crease in DOORS syndrome.
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.
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