DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GM3 synthase deficiency — 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 moduleGM3 synthase deficiency 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 gm3 synthase deficiency 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.
What the evidence adds up to
GM3 synthase deficiency is an autosomal recessive disorder caused by biallelic pathogenic variants in the ST3GAL5 gene, which encodes a sialyltransferase that synthesises ganglioside GM3. Affected individuals exhibit global developmental delay, progressive microcephaly, dyskinetic movements, and profound intellectual disability. Hearing loss and altered skin pigmentation are common. Early clinical features include infantile onset of severe irritability, feeding difficulties, early intractable seizures, growth failure, and hypotonia. A 2018 study of three siblings with a homozygous pathogenic variant described normal birth history followed by developmental stagnation, choreoathetosis, failure to thrive, and visual and hearing impairment; ichthyosis and self-injurious behaviour were newly reported in those patients. The authors concluded that profound intellectual disability, choreoathetosis, and deafness are consistent features, while failure to thrive, epilepsy, regression, vision impairment, and skin findings show variable expressivity.
Most reported ST3GAL5 variants fall within conserved sialyltransferase motifs. A 2022 report described a female with typical features bearing two novel missense variants in motif 3 and motif VS, affecting amino acid residues invariant across the entire GT29 family. Mass spectrometric analysis of her plasma glycolipids confirmed a striking loss of GM3 and accumulation of lactosylceramide and Gb3, with an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient-derived lymphoblasts, indicating that GM3 synthase loss-of-function in that cell type does not impact receptor tyrosine kinase activity. A 2024 study identified compound heterozygous variants in a Chinese boy via trio-whole exome sequencing, including a newly discovered variant c.207-1G>T. That study classified previously reported mutations into R288X and non-R288X groups and found that R288X mutations were more likely to manifest developmental and emotional abnormalities and severe feeding difficulties.
A 2024 report described the generation of a human induced pluripotent stem cell line from fibroblasts of a 13-year-old girl compound heterozygous for two new ST3GAL5 variants, c.1166A>G and c.1024G>A. The hiPSC line showed a normal karyotype, expressed pluripotency markers, and could differentiate into the three germ layers. No clinical trial or therapeutic intervention for GM3 synthase deficiency is described in these abstracts. What remains missing is any funded clinical trial, a viable delivery method for gene therapy or enzyme replacement to the central nervous system, and patient stratification tools to account for the variable expressivity of the 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 Gene Therapy · 2015 · 12 citations
Gene Therapy for Inherited Diseases of Liver Metabolism
AbstractGene therapy is entering the stage of initial clinical development to treat a growing number of inherited metabolic diseases. This review outlines the development of liver-directed gene therapy for diseases caused by deficiencies of enzymes that are primarily expressed in the liver and discusses the disorders that appear most promising for clinical translation.
Compound heterozygous variants within two conserved sialyltransferase motifs of <scp><i>ST3GAL5</i></scp> cause <scp>GM3</scp> synthase deficiency
AbstractAbstract GM3 synthase deficiency (GM3SD) is caused by biallelic variants in ST3GAL5 . The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements. Hearing loss and altered skin pigmentation are also common. Most of the reported variants in ST3GAL5 are found in motifs conserved across all sialyltransferases within the GT29 family of enzymes. These motifs include motif L and motif S which contain amino acids responsible for substrate binding. These loss‐of‐function variants cause greatly reduced biosynthesis of GM3 and gangliosides derived from GM3. Here we describe an affected female with typical GM3SD features bearing two novel variants that reside in the other two conserved sialyltransferase motifs (motif 3 and motif VS). These missense alterations occur in amino acid residues that are strictly invariant across the entire GT29 family of sialyltransferases. The functional significance of these variants was confirmed by mass spectrometric analysis of plasma glycolipids, demonstrating a striking loss of GM3 and accumulation of lactosylceramide and Gb3 in the patient. The glycolipid profile changes were accompanied by an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient‐derived lymphoblasts, indicating that GM3 synthase loss‐of‐function in this cell type does not impact receptor tyrosine kinase activity. These findings demonstrate the high prevalence of loss‐of‐function ST3GAL5 variants within highly conserved sialyltransferase motifs in affected individuals with GM3SD.
Orphanet Journal of Rare Diseases · 2024 · 4 citations · open access
Identification of a novel ST3GAL5 variant in a Chinese boy with GM3 synthase deficiency and literature review of variants in the ST3GAL5 gene
AbstractBACKGROUND: GM3 synthase deficiency (GM3SD) is an autosomal recessive disorder resulting from mutations in the ST3GAL5 gene. It is characterized by intellectual disability, microcephaly, psychomotor and developmental delay, hearing and visual impairments, and changes in skin pigmentation. This study aims to broaden the genetic mutation spectrum of GM3SD through the report of a de novo mutation and a comprehensive summary of GM3SD phenotype to aid in genetic counseling and prenatal diagnosis. RESULTS: Compound heterozygous variants in ST3GAL5 (NM_003896.4: c.1000delC, p.Arg334Glufs*15 and c.207-1G > T, p.Cys70Glufs*81) were identified via trio-whole exome sequencing (trio-WES) and confirmed pathogenic through functional experiments. Notably, c.207-1G > T was a newly discovered variant. Additionally, previously reported GM3SD mutations were classified into R288X and non-R288X, revealing that R288X mutations were more likely to manifest developmental, emotional abnormalities, and severe feeding difficulties. CONCLUSIONS: This study reveals a novel mutation in ST3GAL5 and provides a comprehensive overview of GM3SD phenotype, aiding in the diagnosis and genetic counseling of GM3SD in clinical practice.
Stem Cell Research · 2024 · 1 citations · open access
Generation of a human induced pluripotent stem cell line from a patient with GM3 synthase deficiency using self-replicating RNA vector
AbstractGM3 synthase deficiency (GM3SD) is caused by biallelic variants in the ST3GAL5 gene. Early clinical features of GM3SD include infantile onset of severe irritability and feeding difficulties, early intractable seizures, growth failure, hypotonia, sensorineural hearing impairment. We describe the generation and characterization the human induced pluripotent stem cell (hiPSC) line derived from fibroblasts of a 13-year-old girl with GM3 synthase deficiency resulted compound heterozygous for two new variants in the ST3GAL5 gene, c.1166A > G (p.His389Arg) and the c.1024G > A (p.Gly342Ser). The generated hiPSC line shows a normal karyotype, expresses pluripotency markers, and is able to differentiate into the three germ layers.
Sage Journals Data · 2018 · 0 citations · open access
ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis
AbstractGM3 synthase deficiency is due to biallelic pathogenic variants in <i>ST3GAL5</i>, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in <i>ST3GAL5</i>, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.
Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report
AbstractAbstract Background A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 + 3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naïve CD4+ and CD8+ T-cells, increased number of activated effector memory CD8+ T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient’s cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.
Zeitschrift für Gastroenterologie · 2015 · 0 citations
Determining the molecular consequences of clinically relevant glutamine synthetase mutations
AbstractGlutamine synthetase (GS) catalyzes the ligation of ammonia and glutamate to glutamine under the use of ATP and is, thus, essential for nitrogen metabolism [1,2]. Loss of hepatic GS activity has been linked to serious clinical conditions [3]. In particular, two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death [4]. In a single case known to date, to the best of our knowledge, another GS mutation (R324S) was identified in a neurologically compromised patient [5]. However, the underlying molecular mechanisms of GS deactivation by these mutations have not been understood yet.
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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