DeCure for Hypophosphatemic rickets, X-linked recessive
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hypophosphatemic rickets, X-linked recessive — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHypophosphatemic rickets, X-linked recessive maps to a 1-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 hypophosphatemic rickets, x-linked recessive 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
X-linked hypophosphatemic rickets (XLH) is caused by loss-of-function mutations in the PHEX gene, which encodes a 749-amino acid protein homologous to neutral endopeptidases. In a 1997 study of 29 familial and 14 sporadic cases, mutations were found in 86% of familial and 57% of sporadic cases. A 1998 analysis of 46 unrelated XLH kindreds and 22 nonfamilial patients identified 31 mutations scattered throughout the putative extracellular domain, plus six polymorphisms; over 20% of mutations in nonfamilial patients were de novo. A 2007 Korean study of 15 unrelated patients found eight mutations in nine patients, five of them novel, and noted that skeletal disease tended to be more severe when the mutation was in the C-terminal half of the gene, but no clear genotype-phenotype correlation was established.
The disease is characterised by low serum phosphate, normal calcium, elevated alkaline phosphatase, and low 1,25-dihydroxyvitamin D3. A 2013 case report of a three-year-old boy described phosphate at 0.45 mmol/L, alkaline phosphatase at 1864 IU/L, and typical radiographic changes in distal radius, ulna, and lower limb bones. After treatment with calcitriol and phosphate supplements, laboratory values and radiographic changes resolved. A 2007 review noted that beyond PHEX and FGF23, other genes — NaPiIIc and Dmp1 — can also cause hypophosphatemic rickets, and that improved FGF23 assays and imaging techniques aid diagnosis of tumour-induced osteomalacia.
A 2024 Russian expert council resolution, published in Pediatria, outlines modern diagnostic and treatment approaches for children with XLH, but the abstract provides no new trial data, no survival or response rates, and no mention of any drug beyond calcitriol and phosphate. What remains missing are large prospective trials comparing long-term outcomes of different phosphate and vitamin D analogue regimens, validated biomarkers to guide dosing, and studies that stratify patients by mutation type or severity to determine 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.
Genome Research · 1997 · 163 citations · open access
Genomic Organization of the Human <i>PEX</i> Gene Mutated in X-Linked Dominant Hypophosphatemic Rickets
AbstractX-linked dominant hypophosphatemic rickets (HYP) is the most common form of hereditary rickets. Recently we have cloned the PEX gene and shown it to be mutated and deleted in HYP individuals. We have now completely sequenced a 243-kb genomic region containing PEX and have identified all intron–exon boundary sequences. We show that PEX, homologous to members of a neutral endopeptidase family, has an exon organization that is very similar to neprilysin. We have performed an extensive mutation analysis examining all 22 PEX coding exons in 29 familial and 14 sporadic cases of hypophosphatemia. Sequence changes include missense, frameshift, nonsense, and splice site mutations and intragenic deletions. A mutation was found in 25 (86%) of the 29 familial cases and 8 (57%) of the 14 sporadic cases. Our data provide the first evidence that most of the familial and also a large number of the sporadic cases of hypophosphatemia are caused by loss-of-function mutations in PEX . [The sequence data described in this paper have been submitted to GenBank under accession nos. Y08111 – Y08132 and Y10196 .]
The Journal of Clinical Endocrinology & Metabolism · 1998 · 123 citations · open access
Mutational Analysis of PHEX Gene in X-Linked Hypophosphatemia1
AbstractHypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5'untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.
Journal of Korean Medical Science · 2007 · 47 citations · open access
PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets
AbstractX-linked hypophosphatemic rickets (XLH) results from mutations in the PHEX gene. Mutational analysis of the PHEX gene in 15 unrelated Korean patients with hypophosphatemic rickets revealed eight mutations, including five novel mutations, in nine patients: two nonsense mutations, two missense mutations, one insertion, and three splicing acceptor/donor site mutations. Of these, c.64G>T, c.1699C>T, c.466_467 insAC, c.1174-1G>A, and c.1768+5G>A were novel mutations. To analyze the correlation between genotype and phenotype, phenotypes were compared between groups with and without a mutation, in terms of mutation location, mutation type, and sex. Skeletal disease tended to be more severe in the group with a mutation in the C-terminal half of the PHEX gene, but no genotype-phenotype correlation was detected in other comparisons. Further extensive studies of the PHEX gene mutations and analyses of the genotype-phenotype relationships are required to understand PHEX function and the pathogenesis of XLH.
Current Opinion in Pediatrics · 2007 · 12 citations
Regulation of phosphate homeostasis in infants, children, and adolescents, and the role of phosphatonins in this process
AbstractPURPOSE OF REVIEW: Unlike calcium metabolism, the control of phosphate homeostasis has long been poorly understood. The identification of 'phosphatonins' in the serum of hypophosphatemic patients, the unveiling of the genetic causes of hypo and hyperphosphatemic diseases in patients, and the creation of finely adapted animal models have revolutionized our understanding of phosphate homeostasis. RECENT FINDINGS: Original reports published in 2006/2007 bring valuable pieces of information that enable better understanding of the physiological regulation of phosphate homeostasis by more precisely defining the interplay between PHEX, vitamin D, and phosphatonins; identification of new genes causing hypophosphatemic rickets, aside from PHEX and fgf23, namely the genes encoding for a renal sodium-phosphate cotransporter, NaPiIIc, and for a bone matrix protein, DmpI; and improved diagnosis of tumor-induced osteomalacia with more precise imaging techniques for tumor localization and more precise fibroblast growth factor 23 assays. SUMMARY: From a clinical point of view, these findings offer new tools for the diagnosis of hypophosphatemic rickets (biologic, genetic, imaging techniques) and open the way to new treatment strategies.
AbstractAIM: The aim of this work was the presentation of one case with X-linked hypophosphatemic rickets. METHODS: Diagnosis has been established based on the anamnesis, physical examination, anthropometric measurements, laboratory tests and radiological examination. RESULTS: A male patient (age 3 years) has been hospitalized due to the growth delay, bone deformity, bone pain and walking difficulties. The laboratory tests have revealed that the calcium value was in the reference range, that of phosphates was low (0.45 mmol/L), the alkaline phosphatase value was quite high (1864 IU/L), the value of parathyroid hormone and of 25- hydroxyvitamin D3 were in the reference ranges, whereas the value of 1,25- dihydroxyvitamin D3 was low. Radiographic changes were evident and typical in the distal metaphysis of radius and ulna as well as in the bones of the lower limbs. After treatment with synthetic analog of vitamin D3--calcitriol and phosphates, the above mentioned laboratory test values and the radiographic changes in bones withdrew. CONCLUSION: X- linked hypophosphatemic rickets is a rare disease inherited through X chromosome, and its treatment includes a constant use of calcitriol and phosphates with the aim of avoidance of clinical and laboratory manifestations.
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.
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.
