DeCure for ALG12-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ALG12-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 moduleALG12-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
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 alg12-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
adaptor related protein complex 4 subunit epsilon 1 (AP4E1) — AP4E1 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 9U9I · 4.0 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
ALG12-CDG is not mentioned in any of the provided abstracts. The abstracts cover ALG1-CDG, ALG3-CDG, and ALG11-CDG, as well as general CDG treatment and a proteomics method. No data on ALG12-CDG patients, mutations, biomarkers, or treatments appear in these texts.
The 2016 study on ALG1-CDG reports 39 previously unreported patients from 32 families, adding 26 new mutations to the 13 mutations previously known in 18 patients. Pathogenicity was confirmed by failure to rescue growth or hypoglycosylation in an alg1-deficient yeast strain, but no rank order between biomarker glycosylation and patient phenotype could be established. A protein-linked xeno-tetrasaccharide biomarker was found in all 27 patients tested. The 2020 proteomics paper shows that mutations in ALG1 or ALG2 strongly reduce levels of the ALG1 and ALG2 proteins in patient fibroblasts, while other glycosyltransferases remain unchanged, contradicting the expectation that ALG1, ALG2, and ALG11 form a stable complex.
The 2021 paper on ALG3-CDG describes 10 new individuals with 11 novel variants, bringing the total to 40 reported individuals. It expands the phenotype to include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses showed combined deficiencies of hybrid glycans and extension beyond Man5GlcNAc2, unique to ALG3-CDG. The 2019 ALG11-CDG paper describes two unrelated patients with novel mutations, severe psychomotor disabilities, and epilepsy; one patient had a normal transferrin glycosylation profile, previously unreported in ALG11-CDG.
The 2024 treatment overview states that for most CDGs, only symptom management is available, though recent advances have moved some therapies from research to practical application for certain CDGs. No specific therapy is described for ALG12-CDG. What is missing for ALG12-CDG specifically is any published patient cohort, any validated biomarker, any genotype-phenotype correlation, any quantitative protein data, and any treatment trial. Without these, no evidence exists to support drug repurposing for this ultra-rare disorder.
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 Mutation · 2016 · 58 citations · open access
ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients
AbstractCongenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
Journal of Inherited Metabolic Disease · 2021 · 21 citations · open access
Expanding the phenotype, genotype and biochemical knowledge of <scp>ALG3‐CDG</scp>
AbstractAbstract Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3‐CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3‐CDG based on molecular and biochemical testing with 11 novel variants in ALG3 , bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3‐CDG, we expand the symptomatology of ALG3‐CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N‐glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man 5 GlcNAc 2 consistent with their truncated lipid‐linked precursor oligosaccharides. This spectrum of N‐glycan changes is unique to ALG3‐CDG. These expanded features of ALG3‐CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.
American Journal of Medical Genetics Part A · 2019 · 15 citations · open access
ALG11‐CDG syndrome: Expanding the phenotype
AbstractALG11-Congenital Disorder of Glycosylation (ALG11-CDG, also known as congenital disorder of glycosylation type Ip) is an inherited inborn error of metabolism due to abnormal protein and lipid glycosylation. We describe two unrelated patients with ALG11-CDG due to novel mutations, review the literature of previously described affected individuals, and further expand the clinical phenotype. Both affected individuals reported here had severe psychomotor disabilities and epilepsy. Their fibroblasts synthesized truncated precursor glycan structures, consistent with ALG11-CDG, while also showing hypoglycosylation of a novel biomarker, GP130. Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that has not been reported previously in patients with ALG11-CDG. Together, our data expand the clinical and mutational spectrum of ALG11-CDG.
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.
Lethal COG6‐CDG in neonatal patient with arachnodactyly, joint contractures, and skin manifestations: Founder mutation in the Southeastern European population?
AbstractHerein, we report a lethal case of the ultra-rare COG6-congenital disorder of glycosylation (CDG) presenting with skin manifestations (scaling and erosions) and joint contractures in a neonate of Albanian origin. The patient was homozygous for a COG6 pathogenic variant, previously reported in another three individuals of Greek, Bulgarian and Turkish descent. The presence of a founder mutation in the geographical area is possible. The index case emphasizes the need to consider CDGs in neonatal patients with skin manifestations and joint contractures, particularly patients of Southeastern European or West Asian origin.
bioRxiv (Cold Spring Harbor Laboratory) · 2020 · 1 citations · open access
Targeted Proteomics Reveals Quantitative Differences in Low Abundance Glycosyltransferases of Patients with Congenital Disorders of Glycosylation
AbstractAbstract Protein glycosylation is essential in all domains of life and its mutational impairment in humans can result in severe diseases named Congenital Disorders of Glycosylation (CDGs). Studies on molecular level are however challenging, because many glycosyltransferases in the endoplasmic reticulum (ER) are low abundance membrane proteins. We established a comprehensive multiple reaction monitoring (MRM) assay to quantify most human glycosyltransferases involved in the processes of N -glycosylation, O - and C -mannosylation in the ER. To increase reproducibility, a membrane protein fraction of isotopically labeled HEK 293T cells was used as an internal standard. With this internal standard the MRM assay is easily transferable between laboratories. 22 glycosyltransferases could be reliably quantified from whole cell lysates of HEK 293T cells, HeLa cells and skin fibroblast cell lines. We then analyzed fibroblasts derived from CDG type I patients with mutations in the ALG1 , ALG2 or ALG11 gene. Mutations in ALG1 or ALG2 gene strongly reduced the levels of the ALG1 and ALG2 protein, respectively. In contrast, the levels of all other glycosyltransferases remained unchanged, which was unexpected given evidence that the ALG1, ALG2 and ALG11 proteins form a stable complex. This study describes an efficient workflow for the development of MRM assays for low abundance proteins, establishes a ready-to-use tool for the comprehensive quantification of ER-localized glycosyltransferases and provides new insight into the organization of disease-relevant glycosylation processes.
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.
