DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hypotonia-cystinuria syndrome — 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 moduleHypotonia-cystinuria syndrome 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 hypotonia-cystinuria 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
calmodulin-lysine N-methyltransferase (CAMKMT) — CAMKMT 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 sahdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4PWY · 1.9 Å · ligand S-ADENOSYL-L-HOMOCYSTEINE (SAH). Experimental structure, not a prediction.
What the evidence adds up to
Two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the cystinuria gene SLC3A1, have been described. They display a phenotype similar to atypical hypotonia-cystinuria syndrome with growth failure and neuro-muscular features, but without cystinuria. They also exhibit features not previously reported, such as cleft palate and genital abnormalities. This is the first report of patients with a homozygous 2p21 deletion syndrome without cystinuria, further delineating the complex genotype-phenotype correlations of homozygous microdeletion syndromes in this region.
Hypotonia-cystinuria syndrome itself is characterised by infantile hypotonia, poor feeding, growth hormone deficiency, and cystinuria. It is caused by a homozygous contiguous deletion of two genes: SLC3A1 (mutations of which cause cystinuria type I) and PREPL. The syndrome resembles Prader-Willi syndrome, with severe hypotonia at birth, nephrolithiasis due to cystinuria, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. The function of PREPL and how its deletion causes this Prader-Willi-like disorder remains unclear. Larger deletions involving these two genes and neighbouring genes are associated with more severe and extended phenotypes.
Cystinosis, a different disease of childhood characterised by dwarfism and accumulation of cystine crystals in many tissues, is not to be confused with cystinuria. Cystinosis involves generalised aminoaciduria and renal tubular dysfunction, often manifesting as acidosis, hypokalemia, and impaired water reabsorption, with renal rickets and uremia as frequent late sequelae. Cystinuria, in contrast, results from a lowered renal threshold for cystine, lysine, and arginine and does not reflect a general disturbance of amino acid metabolism.
What is still missing is a clear understanding of how PREPL deletions cause the Prader-Willi-like phenotype, and whether mutations of PREPL alone can cause the syndrome without cystinuria — this has not yet been reported. No treatment trials exist for hypotonia-cystinuria syndrome, and no patient stratification or funding for such studies has been described.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2013 · 57 citations
Further delineation of genotype–phenotype correlation in homozygous 2p21 deletion syndromes: First description of patients without cystinuria
AbstractHomozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region.
AbstractCystinosis, or the Lignac-Fanconi syndrome, is a disease of childhood that is characterized by dwarfism and by the accumulation of cystine crystals within many tissues of the body. Investigation reveals a generalized aminoaciduria and renal tubular dysfunction, which is usually manifest by acidosis, hypokalemia, and impaired water reabsorption. Renal rickets and uremia are frequent late sequelae. While the disturbance is believed to be a hereditary defect in the utilization of many amino acids, cystine precipitates out, presumably because of its low solubility. The condition is not to be confused with the relatively benign cystinuria which appears to result from a lowered renal threshold (for cystine, lysine, and arginine) and which does not reflect a general disturbance of amino acid metabolism, such as is the case with the cystinosis of children. The ophthalmologic importance of cystinosis is due to the fact that the crystals of cystine can be frequently seen in
Developmental Medicine & Child Neurology · 2011 · 2 citations · open access
Evaluation of the pediatric patient with hypotonia: don’t forget the hypotonia‐cystinuria syndrome!
AbstractSIR–We have read with interest the very useful review on genetic evaluation of a pediatric patient with hypotonia by Lisi and Cohn.1 To this discussion we would like to add the hypotonia-cystinuria syndrome (HCS), which is caused by a homozygous contiguous deletion of two genes: SLC3A1 (mutations which cause cystinuria type I) and PREPL.2 HCS resembles Prader-Willi syndrome (PWS), and is characterized by generalized, severe hypotonia at birth, nephrolithiasis due to cystinuria, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. The function of PREPL and how deletions of this gene cause this PWS-like disorder is still unclear.3 Larger deletions involving these two as well as neighbouring genes also exist and are associated with more severe and extended phenotypes.4 HCS can be easily diagnosed by urinary amino acid analysis. We would therefore suggest adding urinary amino acid analysis (and not only plasma amino acid analysis) to the evaluation of patients with hypotonia to allow for the detection of HCS. Theoretically, this syndrome (without the cystinuria) could also be caused by mutations of the PREPL gene alone but this has not been reported yet. HCS should be considered in patients with a PWS-like phenotype without the typical chromosomal abnormality of PWS.
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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