DeCure for SLC35A2-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for SLC35A2-congenital disorder of glycosylation — 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 moduleSLC35A2-congenital disorder of glycosylation 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
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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 slc35a2-congenital disorder of glycosylation 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
SRY-box transcription factor 11 (SOX11) — SOX11 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6T78 · 2.504 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
SLC35A2-CDG is an X-linked congenital disorder of glycosylation caused by mutations in the UDP-galactose transporter SLC35A2. As of 2018, only 10 patients had been reported. A 2018 case report describes a 27-month-old girl with developmental delay, central hypotonia, cerebral atrophy, and failure to thrive with growth retardation, identified by whole exome sequencing as having a mosaic missense variant (c.991G>A) in SLC35A2. This patient did not have seizures, and growth hormone testing indicated sufficiency. Importantly, transferrin isoform analysis, the standard screening test for congenital disorders of glycosylation, did not identify her condition, meaning normal transferrin results do not rule out SLC35A2-CDG.
A 2019 functional study tested eight disease-associated SLC35A2 mutations using a cell-based rescue assay that measured expression of the glycosphingolipid globotriaosylceramide (Gb3), the receptor for Shiga toxins. Two mutations (S213F and G282R) completely inhibited SLC35A2 function, and three (R55L, G266V, S304P) caused partial inhibition. However, three other mutations (V331I, V258M, Y267C) did not impair transporter activity in this assay, suggesting that for some variants the disease mechanism may involve factors beyond simple loss of UDP-galactose transport.
A 2021 review of congenital disorders of glycosylation with defective fucosylation notes that only five fucosylation-related CDG types have been described (FUT8-CDG, FCSK-CDG, POFUT1-CDG, SLC35C1-CDG, GFUS-CDG), and discusses fucose therapy approaches for those defects. SLC35A2-CDG is not a fucosylation defect, and this review does not address its treatment. A 2024 overview of CDG treatments states that for most congenital disorders of glycosylation, management remains symptomatic rather than curative, though some recent advances have moved from research to practical application for certain CDG types.
What is still missing for SLC35A2-CDG specifically: no dedicated clinical trial has been reported, no therapy targeting the underlying transporter defect has been tested in patients, and the small number of identified cases (fewer than 20) limits the ability to stratify patients by mutation type or mosaic status. Funding for natural history studies and development of a reliable biomarker beyond transferrin analysis would be needed before any treatment trial could be designed.
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 Inherited Metabolic Disease · 2021 · 27 citations · open access
Congenital disorders of glycosylation with defective fucosylation
AbstractFucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of all hitherto known 25 patients affected with those defects with regard to their pathophysiology and genotype. In addition, we describe five new patients with novel variants in the SLC35C1 gene. Furthermore, we discuss the efficacy of fucose therapy approaches within the different defects.
Molecular Genetics and Metabolism · 2024 · 12 citations · open access
Treatment of congenital disorders of glycosylation: An overview
AbstractWhile the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.
Functional analyses of the UDP-galactose transporter SLC35A2 using the binding of bacterial Shiga toxins as a novel activity assay
AbstractSLC35A2 transports UDP-galactose from the cytosol to the lumen of the Golgi apparatus and endoplasmic reticulum for glycosylation. Mutations in SLC35A2 induce a congenital disorder of glycosylation. Despite the biomedical relevance, mechanisms of transport via SLC35A2 and the impact of disease-associated mutations on activity are unclear. To address these issues, we generated a predicted structure of SLC35A2 and assayed for the effects of a set of structural and disease-associated mutations. Activity assays were performed using a rescue approach in ΔSLC35A2 cells and took advantage of the fact that SLC35A2 is required for expression of the glycosphingolipid globotriaosylceramide (Gb3), the cell surface receptor for Shiga toxin 1 (STx1) and 2 (STx2). The N- and C-terminal cytoplasmic loops of SLC35A2 were dispensable for activity, but two critical glycine (Gly-202 and Gly-214) and lysine (Lys-78 and Lys-297) residues in transmembrane segments were required. Residues corresponding to Gly-202 and Gly-214 in the related transporter SLC35A1 form a substrate-translocating channel, suggesting that a similar mechanism may be involved in SLC35A2. Among the eight disease-associated mutations tested, SLC35A2 function was completely inhibited by two (S213F and G282R) and partially inhibited by three (R55L, G266V, and S304P), providing a straight-forward mechanism of disease. Interestingly, the remaining three (V331I, V258M, and Y267C) did not impact SLC35A2 function, suggesting that complexities beyond loss of transporter activity may underlie disease due to these mutations. Overall, our results provide new insights into the mechanisms of transport of SLC35A2 and improve understanding of the relationship between SLC35A2 mutations and disease.
Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report
AbstractAbstract Background Congenital disorders of glycosylation are rare conditions caused by genetic defects in glycan synthesis, processing or transport. Most congenital disorders of glycosylation involve defects in the formation or transfer of the lipid-linked oligosaccharide precursor of N-linked glycans. SLC35A2-CDG (previously CDG-IIm) is caused by hemizygous or heterozygous mutations in the X-linked gene SLC35A2 that encodes a UDP-galactose transporter. To date there have only been 10 reported patients with SLC35A2 mutations. Importantly, the patient presented here was not identified in infancy by transferrin isoform analysis, the most common testing to identify patients with a congenital disorder of glycosylation. Case presentation A 27Â month old girl with developmental delay, central hypotonia, cerebral atrophy, and failure to thrive with growth retardation was identified by whole exome sequencing to have a mosaic missense variant in SLC35A2 (c.991Gâ >â A). This particular variant has been previously reported in a male as a mutation. Comparison of all clinical findings and new information on growth pattern, growth hormone testing and neurodevelopmental evaluation are detailed on the patient presented. Conclusion This patient report increases the clinical and scientific knowledge of SLC35A2-CDG, a rare condition. New information on reduced growth, growth hormone sufficiency, lack of seizures, and neurodevelopmental status are presented. This new information will be helpful to clinicians caring for individuals with SLC35A2-CDG. This report also alerts clinicians that transferrin isoform measurements do not identify all patients with congenital disorders of glycosylation.
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.
