DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ocular albinism — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleOcular albinism maps to a 4-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 ocular albinism 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
adaptor related protein complex 3 subunit delta 1 (AP3D1) — AP3D1 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 gtpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9C59 · 4.3 Å · ligand GUANOSINE-5'-TRIPHOSPHATE (GTP). Experimental structure, not a prediction.
What the evidence adds up to
Ocular albinism type 1 is an X-linked disorder caused by mutations in the GPR143 gene, which encodes a G protein-coupled receptor expressed in the retinal pigment epithelium and melanocytes. A 2000 study expressed 19 independent missense mutations of the OA1 gene in COS-7 cells and found two distinct biochemical defects. Eleven of the 19 mutants (approximately 60%) were retained in the endoplasmic reticulum, showing defective intracellular transport and glycosylation consistent with protein misfolding. The remaining eight mutants (approximately 40%) displayed sorting and processing indistinguishable from wild-type protein, and most of these mutations clustered within the second and third cytosolic loops, regions critical for G protein-coupling and effector activation in canonical GPCRs. The study concluded that protein misfolding is a major pathogenic mechanism in OA1.
A 2015 report described a Chinese trio-family in which a boy with X-linked ocular albinism carried a novel missense mutation, c.494C>A (p.Ala165Asp), in GPR143. The mutation was also present in his mother but absent in his father and 50 unrelated controls. The boy exhibited mild fundus hypopigmentation and nystagmus appearing at 4 months of age, with normal iris pigmentation. His mother showed foveal hypoplasia and a characteristic leopard-like fundus. The mutation is predicted to affect the fourth transmembrane domain, and computational tools classified it as damaging. The authors noted that missense mutations account for over 40% of all GPR143 mutations, and that most mutations in various ethnicities occur in exons 1, 2, 3, 7 or 8, whereas this mutation occurred in exon 4.
A 2018 review noted that all forms of albinism, regardless of the causative gene, produce the same retinal pathology, and that the causative genes are not expressed in the neurosensory retina. The review raised the possibility that all forms of albinism funnel through the same final common pathway. It mentioned a potential way to treat the disease and restore normal retinal development, but provided no experimental data, no tested compound, and no clinical results.
No drug treatment for ocular albinism has been tested in any clinical trial reported in these abstracts. What is missing is any funded clinical development programme, any candidate molecule shown to rescue the trafficking or signalling defects of OA1 mutants in vivo, and any understanding of how to stratify patients by mutation type (misfolding versus signalling-defective) for a future trial.
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 Molecular Genetics · 2000 · 70 citations · open access
Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1
AbstractOcular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes. Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations. Eleven of the nineteen OA1 mutants (approximately 60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (approximately 40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure-function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.
Journal of Neuroscience Research · 2018 · 45 citations
Pigmentation and vision: Is GPR143 in control?
AbstractAlbinism, typically characterized by decreased melanin synthesis, is associated with significant visual deficits owing to developmental changes during neurosensory retina development. All albinism is caused by genetic mutations in a group of diverse genes including enzymes, transporters, G-protein coupled receptor. Interestingly, these genes are not expressed in the neurosensory retina. Further, regardless of cause of albinism, all forms of albinism have the same retinal pathology, the extent of which is variable. In this review, we explore the possibility that this similarity in retinal phenotype is because all forms of albinism funnel through the same final common pathway. There are currently seven known genes linked to the seven forms of ocular cutaneous albinism. These types of albinism are the most common, and result in changes to all pigmented tissues (hair, skin, eyes). We will discuss the incidence and mechanism, where known, to develop a picture as to how the mutations cause albinism. Next, we will examine the one form of albinism which causes tissue-specific pathology, ocular albinism, where the eye exhibits the retinal albinism phenotype despite near normal melanin synthesis. We will discuss a potential way to treat the disease and restore normal retinal development. Finally, we will briefly discuss the possibility that this same pathway may intersect with the most common cause of permanent vision loss in the elderly.
Acta Ophthalmologica · 2015 · 8 citations · open access
A novel mutation, c.494C>A (p.Ala165Asp), in the <i><scp>GPR</scp>143</i> gene causes a mild phenotype in a Chinese X‐linked ocular albinism patient
AbstractX-linked ocular albinism (OMIM #300500) is a monogenic disease characterized by hypopigmentation of the fundus. The affected are predominantly males, and their mothers are the mutation carriers. The patients usually have severely impaired visual acuity, marked photophobia and variable strabismus. The first sign of the disease is mostly nystagmus that usually appears 2 or 3 months after birth. Interestingly, this form of albinism particularly affects the eyes, and the pigmentation of hair and skin is usually normal (Levin & Stroh 2011). To date, only one gene, GPR143 (OMIM #300808), has been identified as a causal agent for X-linked ocular albinism. This gene, located on chromosome Xp22.3, encodes a G protein-coupled receptor that binds tyrosine, L-DOPA and dopamine and plays a role in melanosome biogenesis, organization and transport (Palmisano et al. 2008). The gene is expressed at high levels in the retinal pigment epithelium and in melanocytes. Here, we report a Chinese trio-family with the son who was affected by the X-linked ocular albinism in which a novel missense mutation in the GPR143 was observed. The boy exhibited particularly mild hypopigmentation in the fundus and nystagmus that appeared at 4 months of age. Clinical examinations at 7 months of age revealed hypopigmentation of the fundus and foveal hypoplasia (Fig 1A: a-b). The fundus hypopigmentation was mild, and the pigmentation of the iris was normal compared with other Chinese people. In his mother, foveal hypoplasia and characteristic leopard-like fundus, which is a typical pathological appearance of hypopigmentation of retinal pigment epithelium, were observed (Fig 1A: c-d). No abnormalities were observed in the father (Fig 1A: e-f). After obtaining informed consent, we performed genetic analyses of the family. Genomic DNA was extracted from peripheral blood leucocytes. Sanger sequencing on PCR products covering all exons and intron–exon boundaries in both directions was employed to detect mutations in the GPR143. The novel missense mutation, c.494C>A (p.Ala165Asp), in GPR143 was identified in both the boy and his mother (Fig 1B). The mutation was absent in his father and in 50 unrelated normal control subjects. Evolutionary conservation was tested by comparing the wild-type residue in the encoded protein from five different species, including macaca mulatta, mouse, rat, chicken and Danio rerio using the CLUSTALW tool (Fig 1C). A structural model of the wild-type protein was built using the GPCR-I-TASSERserver (Zhang et al. 2015), and the figure was prepared by PyMOL (http://www.pymol.org/). Ala165 is predicted on the forth transmembrane and facing inward (Fig 1D). Therefore, substitution with a large hydrophilic residue Asp at this site could affect the structure folding function of GPR143. A mutation in the adjacent residue, Thr166, was found in OA1 patients and speculated to cause structural and functional changes to GPR143 (Mayeur et al. 2006). The mutation c.494C>A (p.Ala165Asp) was predicted to be ‘damaging’ by the SIFT (http://sift.jcvi.org/). This mutation therefore is likely to be responsible for the patient's ocular albinism. Mutations responsible for this disease in the gene have been registered in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php) are the missense mutations, splice site mutations, small deletions insertions, gross deletions and complex arrangements. Among these mutations, missense mutations are most common and account for over 40% mutations in total. These mutations either cause misfolding of the protein or affect the receptor interaction with the associated G protein. Notably, the novel mutation c.494C>A (p.Ala165Asp) was associated with mild hypopigmentation and the patient's normal iris pigmentation. Moreover, the location of the mutation was uncommon. It occurred in exon 4, but not exons 1, 2, 3, 7 or 8 where most mutations occur among various ethnicities, including the Chinese, blacks and whites (Fang et al. 2008). Actually, only a few GPR143 gene mutations associated with X-linked ocular albinism have been identified in the Chinese population. The finding in our study has expanded the mutational spectrum of GPR143.
Journal of the Foundations of Ophthalmology · 2025 · 0 citations
Oculocutaneous Albinism: An Overview
AbstractAlbinism encompasses a group of heterogenous genetic conditions affecting the melanin synthesis pathway leading to a reduction or absence in melanin production. In ophthalmology, albinism can be broadly categorised into two groups: oculocutaneous albinism (OCA) and ocular albinism (OA). In OCA, hypopigmentation involves the skin, hair, and eyes, whereas in OA pigmentary changes are limited to ocular structures, primarily the iris and retina. Both OA and OCA are rare disorders that share similar characteristic ocular findings and visual challenges. This article focuses on oculocutaneous albinism.
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.
