DeCure for Autosomal dominant nonsyndromic hearing loss 2A
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal dominant nonsyndromic hearing loss 2A — 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 moduleAutosomal dominant nonsyndromic hearing loss 2A 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 autosomal dominant nonsyndromic hearing loss 2a 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
potassium voltage-gated channel subfamily Q member 4 (KCNQ4) — KCNQ4 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 2rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7BYL · 2.5 Å · ligand [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho
ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate (PT5). Experimental structure, not a prediction.
What the evidence adds up to
In a Chinese cohort of 3,864 patients, 106 (2.74%) carried either a homozygous p.V37I mutation in GJB2 or a compound p.V37I plus another GJB2 pathogenic mutation, a frequency significantly higher than in 600 controls (0%). Hearing loss in these patients ranged from mild to profound, but most (66.04%) had mild or moderate loss. No difference in hearing level distribution was found between the homozygous and compound groups. The authors concluded that p.V37I is definitely related to deafness and that the milder phenotype should be considered by otolaryngologists.
Two novel TECTA mutations were identified in two Korean families with autosomal dominant nonsyndromic sensorineural hearing loss. The mutation c.3995G>T (p.C1332F) in the von Willebrand factor type D3-D4 interdomain was associated with stable high-frequency loss; the mutation c.5618C>T (p.T1873I) in the zona pellucida domain was associated with stable mid-frequency loss. The cysteine-to-phenylalanine change was not related to progression, which the authors note argues against a previous hypothesis. They propose that patients with missense mutations in the vWFD3-D4 interdomain may be candidates for middle ear implantation. TECTA mutations account for about 4% of autosomal dominant nonsyndromic hearing loss in some populations.
A large North American family with autosomal dominant progressive sensorineural hearing loss was evaluated in 1996. Hearing loss began at about age 20 and became profound by approximately age 45. The report describes the mutation as causing nonsyndromic, autosomal-dominant progressive loss, but no specific gene or drug intervention is mentioned.
A 2020 review notes that 119 nonsyndromic genes have been associated with hearing loss in children, and that identifying genotype-phenotype correlations improves diagnosis and prognosis. Gene therapy is described as emerging and possibly viable in the future, but no clinical trial results are given. A 2000 German review states that 11 genes for autosomal dominant and 6 for autosomal recessive hearing loss had been isolated at that time, and estimates that 50 to 80 hearing loss genes remain undiscovered.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PLoS ONE · 2015 · 43 citations · open access
The Relationship between the p.V37I Mutation in GJB2 and Hearing Phenotypes in Chinese Individuals
AbstractThe most common cause of nonsyndromic autosomal recessive hearing loss is mutations in GJB2. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in GJB2 and the hearing phenotype is controversial. Among the 3,864 patients in this study, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). The hearing loss phenotype ranged from mild to profound in all patients with the homozygous p.V37I variation or compound p.V37I plus other GJB2 pathogenic mutation. There was no difference in the distribution of the hearing level in the group with the homozygous p.V37I variation and the group with the compound p.V37I variation plus pathogenic mutation. Most patients (66.04%) with the V37I-homozygous variation or p.V37I plus other pathogenic mutation had a mild or moderate hearing level. This study found a definite relationship between p.V37I and deafness, and most patients who carried the pathogenic combination with p.V37I mutation had mild or moderate hearing loss. Therefore, otolaryngologists should consider that the milder phenotype might be caused by the GJB2 p.V37I mutation.
American Journal of Audiology · 1996 · 24 citations
Autosomal-Dominant Progressive Sensorineural Hearing Loss in a Large North American Family
AbstractForty-nine members of a family with autosomal-dominant progressive sensorineural hearing loss were evaluated by audiologists, otologists, and geneticists. The results presented here show a nonsyndromic, autosomal-dominant mutation causing progressive sensorineural hearing loss beginning at about age 20 and becoming profound by approximately age 45. Because of the unambiguous nature of the hearing loss, the size of the family, and the availability of two previously described temporal bones from family members, a fairly complete description of the nature and impact of this mutation will be presented.
Novel <b><i>TECTA </i></b>Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications
AbstractTECTA is a causative gene of autosomal dominant (DFNA8/A12) and autosomal recessive (DFNB 21) nonsyndromic sensorineural hearing loss (NSHL). Mutations in TECTA account for 4% of all autosomal dominant NSHL cases in some populations and are thus thought to be one of the major causes of autosomal dominant NSHL. A genotype-phenotype correlation for autosomal dominant mutations in the TECTA gene has been proposed. Two families (SB146 and SB149), which segregated moderate NSHL in an autosomal dominant fashion, were included in this study. We performed targeted resequencing of 134 known deafness genes (TRS-134) and bioinformatics analyses to find causative mutations for NSHL in these 2 families. Through TRS-134, we detected 2 novel mutations, i.e. c.3995G>T (p.C1332F) and c.5618C>T (p.T1873I), in the TECTA gene. These mutations cosegregated with NSHL in the studied families and were not detected in normal controls. The mutations c.3995G>T and c.5618C>T reside in the von Willebrand factor type D3-D4 (vWFD3-D4) interdomain of the zonadhesin (ZA) domain and the zona pellucida (ZP) domain, respectively. p.C1332F is the first mutation detected in the vWFD3-D4 interdomain of the ZA domain. The mutations p.C1332F and p.T1873I were associated with stable high-frequency and mid-frequency hearing loss, respectively. Notably, the cysteine residue mutated to phenylalanine in SB146 was not related to progression of sensorineural hearing loss, which argues against the previous hypothesis. Here we confirm a known genotype-phenotype correlation for the ZP domain and propose a hypothetical genotype-phenotype correlation which relates mutations in vWFD3-D4 to stable high-frequency NSHL in Koreans. This clinical feature makes subjects with the missense mutation in the vWFD3-D4 interdomain of TECTA potentially good candidates for middle ear implantation.
Genetics of pediatric hearing loss: A functional perspective
AbstractOBJECTIVES: This article reviews the current role of genetics in pediatric hearing loss (HL). METHODS: A review of the current literature regarding the genetic basis of HL in children was performed. RESULTS: To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. CONCLUSIONS: Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.
Zurich Open Repository and Archive (University of Zurich) · 2000 · 0 citations · open access
Erbliche Schwerhörigkeit: neue Möglichkeiten der Diagnostik
AbstractMutations in many different genes can result in hearing loss. Using different molecular genetic methods, the disease-causing gene mutations can often be identified or at least localised to defined regions of the genome. These new diagnostic possibilities result from the localisation and identification of a number of hearing-loss genes in the last five years. Diagnostic investigations should always be accompanied by a genetic counselling of the family. In addition, the isolation thus far of 11 genes mutated in autosomal dominant inherited hearing loss, as well as of 6 genes mutated in autosomal recessive inherited hearing loss, has contributed to a better understanding of the molecular pathology of hearing loss in general. However, we are only beginning to see the whole picture, as an estimated 50 to 80 hearing loss genes remain to be discovered.
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.
