DeCure for X-linked dominant hypophosphatemic rickets
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for X-linked dominant hypophosphatemic rickets — 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 moduleX-linked dominant hypophosphatemic rickets 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 x-linked dominant hypophosphatemic rickets 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
Cl-/H+ antiporter 5 (CLCN5) — CLCN5 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 2JA3 · 3.05 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
A 2014 case report describes a two-year-old Turkish girl with a sporadic, de novo 13 bp deletion at the donor splice site of PHEX exon 5 (c.663+12del). This mutation caused the splicing machinery to skip the normal donor site and use two nearby cryptic donor sites, producing two shorter transcripts that both led to frameshifts and non-functional protein. The patient presented with inability to walk, leg bowing, and growth retardation; lab findings showed normal calcium, low phosphate, elevated alkaline phosphatase, and low renal phosphate reabsorption. She was treated with calcitriol 0.5 mg/kg/day and oral phosphate supplement and had a good response. Her parents did not carry the mutation.
A 2018 study identified two novel PHEX variants in two unrelated Chinese families with X-linked hypophosphatemic rickets. In Family 1, a missense variant c.1721T>A (p.Ile574Lys) was found in exon 17. In Family 2, a splicing variant c.591A>G in exon 5 caused a 77 bp deletion at the 3' end of exon 5 during splicing. Quantitative PCR showed that the affected male with the splicing variant had normal PHEX gene expression, while the affected female had low expression compared to normal females. Prenatal diagnosis was performed for fetuses in both families using amniotic fluid; one fetus without the missense variant was confirmed healthy one month after birth.
A 2024 Russian expert council resolution and a 2015 review article are cited but provide no new patient data, treatment outcomes, or drug results. The 2015 review notes that X-linked hypophosphatemic rickets is the most common hereditary rickets, is easily misdiagnosed, and that its treatment is more complicated than that of general rickets, but gives no specific numbers.
What remains missing are large, prospective trials comparing conventional therapy (calcitriol and phosphate) with newer targeted agents such as burosumab, standardised outcome measures for growth and skeletal deformity, and systematic data on long-term renal function and quality of life. No trial has yet stratified patients by specific PHEX mutation type to see whether genotype predicts treatment response.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Pediatric Endocrinology and Metabolism · 2014 · 8 citations
Hypophosphatemic rickets caused by a novel splice donor site mutation and activation of two cryptic splice donor sites in the PHEX gene
AbstractX-linked hypophosphatemic rickets (XLH) is the most common inherited form of rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in a sporadic Turkish girl with hypophosphatemic rickets. The patient was 2 years of age with a complaint of inability to walk. She had bowing of legs and growth retardation. Laboratory data showed normal calcium, low phosphate with markedly elevated ALP, and low phosphate renal tubular reabsorption. She was treated with Calcitriol 0.5 mg/kg/day and oral phosphate supplement with good response. The entire coding region of PHEX gene was sequenced from patient's peripheral leukocyte DNA and a novel 13 bp deletion at the donor splice site of exon5 was found (c.663+12del). Instead of using the donor splice site of intron 4 to splice out exon 5 and intron 5, the spliceosome utilized two nearby cryptic donor splice sites (5' splice site) to splice out intron 4, resulting in two smaller transcripts. Both of them could not translate into functional proteins due to frameshift. Her parents did not carry the mutation, indicating that this is a de novo PHEX mutation likely resulting from mutagenesis of X chromosome in paternal germ cells. We conclude that c.663+12del is a novel mutation that can activate nearby cryptic 5' splice sites. The selection of cryptic 5' splice sites adds the complexity of cell's splicing mechanisms. The current study extends the database of PHEX mutation and cryptic 5' splice sites.
International Journal of Molecular Medicine · 2018 · 6 citations · open access
Two novel variants of the PHEX gene in patients with X‑linked dominant hypophosphatemic rickets and prenatal diagnosis for fetuses in these families
AbstractX‑linked hypophosphatemic rickets (XLHR; OMIM 307800) is an X‑linked dominant disorder caused by mutations in the phosphate‑regulating neutral endopeptidase homolog X‑linked (PHEX) gene, which is located at Xp22.11. In the present study, two novel variants of the PHEX gene were identified in two unrelated families with XLHR by directly sequencing all 22 exon regions and intron/exon boundaries of the PHEX gene. One missense variant, NM_000444.5: c.1721T>A, was identified in exon 17 of the PHEX gene in Family 1, which led to an amino acid change in the p.Ile574Lys protein. The other splicing variant identified was NM_000444.5: c.591A>G, in exon 5 in Family 2, resulting in a deletion of 77 bp in the 3' site of exon 5 during splicing, which was verified by direct cDNA sequencing of the PHEX gene. According to the results of reverse transcription‑quantitative polymerase chain reaction analysis, the affected male with the splicing variant c.591A>G showed normal gene expression of PHEX, whereas the affected female exhibited low gene expression, compared with normal females. Based on these findings, prenatal diagnoses were made for the fetuses with a family history of XLHR using the backup amniotic fluid samples. One fetus without the missense variant was confirmed to be a healthy girl in a follow‑up visit 1 month following birth.
PEDIATRIA Journal named after G N SPERANSKY · 2024 · 1 citations
RESOLUTION BY THE EXPERT COUNCIL: "MODERN APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CHILDREN WITH X-LINKED HYPOPHOSPHATEMIC RICKETS," DATED DEC. 22, 2023. MOSCOW, RUSSIA
AbstractFor citation: S.V. Papizh, V.M. Kenis, A.N. Tsygin, E.K. Petrosyan, S.V. Bochenkov, A.E. Lavrova, T.M. Pervunina, E.V. Rakitskaya, K.S. Kulikova. Resolution by the Expert Council: “Modern approaches to the diagnosis and treatment of children with X-linked hypophosphatemic rickets,” dated Dec. 22, 2023. Moscow, Russia. Pediatria n.a. G.N. Speransky. 2024; 103 (2): 129-136. DOI: 10.24110/0031-403X-2024-103-2-129-136.
International journal of pediatrics · 2015 · 0 citations
Progress in the diagnosis and treatment of X-linked hypophosphatemic rickets
AbstractX-linked hypophosphatemic rickets is the most common hereditary rickets and easy to misdiagnosis or missed.The treatment is more complicated compared with the general rickets.In this paper, the clinical features, genes and treatment of X-linked hypophosphatemic rickets are reviewed.
Key words:
X-linked hypophos-phatemic rickets; PHEX gene; Growth hormone
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.
