Affinage

B3GLCT

Beta-1,3-glucosyltransferase · UniProt Q6Y288

Length
498 aa
Mass
56.6 kDa
Annotated
2026-06-09
16 papers in source corpus 6 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

B3GLCT is an endoplasmic reticulum-resident β1,3-glucosyltransferase that operates within a substrate quality-control pathway for thrombospondin type 1 repeat (TSR)-containing proteins (PMID:28926587, PMID:31600785). It catalyzes transfer of glucose via a β1-3 linkage onto O-linked fucose attached to TSRs, acting sequentially after POFUT2 to complete a glucose-β1,3-fucose disaccharide on properly folded TSRs (PMID:28926587, PMID:31600785). This disaccharide stabilizes the TSR fold and promotes secretion of a specific subset of TSR-containing proteins: ADAMTS20 is highly dependent on B3GLCT, ADAMTS9 is partially dependent, and SCO-spondin (SSPO) requires the modification for efficient secretion, with loss causing intracellular accumulation and elevated BiP indicative of a folding/quality-control defect (PMID:31600785, PMID:33909046). The dependence is substrate-specific — thrombospondin 1 (TSP1) loses its glucose-fucose modification upon B3GLCT loss yet is secreted normally, with a compensatory increase in TSR C-mannosylation (PMID:34695439). Through this role, B3GLCT loss perturbs ADAMTS9/ADAMTS20-dependent ependymal cilia basal body organization and translational polarity (PMID:33909046). Biallelic truncating mutations in B3GLCT cause Peters Plus syndrome, a congenital disorder of glycosylation, including via splice mutations that trigger nonsense-mediated decay (PMID:16909395, PMID:23954224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2006 Medium

    Established B3GLCT as a disease gene by linking biallelic truncating mutations to Peters Plus syndrome, framing it as a glycosylation-defect malformation syndrome before its catalytic activity was directly tested.

    Evidence aCGH and mutation analysis identifying biallelic truncating mutations in 20/20 patients

    PMID:16909395

    Open questions at the time
    • Enzymatic activity inferred from homology, not measured
    • No substrate identified at this stage
    • Mechanism connecting gene loss to phenotype unknown
  2. 2013 Medium

    Clarified one molecular route to loss of function by showing a splice-site mutation causes exon skipping, frameshift, and predicted nonsense-mediated decay, defining how patient mutations abolish the gene product.

    Evidence Ex vivo RT-PCR of patient-derived cells with bioinformatic NMD prediction

    PMID:23954224

    Open questions at the time
    • NMD inferred bioinformatically rather than measured directly
    • Single-lab, single-allele analysis
  3. 2017 High

    Provided the first direct biochemical proof that B3GLCT is a glucosyltransferase, resolving whether the homology-based annotation reflected real catalytic activity on TSRs.

    Evidence In vitro glucosylation assay transferring glucose from UDP-glucose to an O-fucosylated TSR substrate, with TALEN knockouts in zebrafish showing complete loss of activity

    PMID:28926587

    Open questions at the time
    • Did not define which physiological proteins depend on the modification
    • Structural basis of TSR recognition not addressed
  4. 2019 High

    Placed B3GLCT in a sequential POFUT2-then-B3GLCT pathway and revealed substrate selectivity, showing that disaccharide completion is essential for only a subset of TSR proteins.

    Evidence Two independent mouse B3glct knockout alleles with genetic epistasis and biochemical analysis of ADAMTS9 and ADAMTS20 secretion

    PMID:31600785

    Open questions at the time
    • Molecular basis for differential substrate sensitivity not defined
    • Range of full substrate repertoire incomplete
  5. 2021 High

    Defined the cellular consequence of B3GLCT loss as an ER folding/quality-control defect for SSPO and connected substrate misregulation to ependymal cilia organization, linking the molecular activity to tissue phenotype.

    Evidence B3glct mutant cell secretion assays with SSPO glycosylation analysis and BiP co-localization; mouse KO ependymal imaging and substrate mRNA in situ hybridization

    PMID:33909046

    Open questions at the time
    • BiP upregulation establishes folding stress but not the precise quality-control mechanism
    • Causal chain from substrate loss to cilia defects partly correlative
  6. 2021 High

    Demonstrated that B3GLCT modification is not universally required for secretion by showing TSP1 loses the glucose-fucose modification yet is secreted normally, sharpening the substrate-specific model.

    Evidence B3GLCT knockout RPE cells with glycopeptide mass spectrometry and secretion assays including TNFα stimulation and HEK293T overexpression

    PMID:34695439

    Open questions at the time
    • Why TSP1 escapes secretion dependence is unexplained
    • Functional significance of compensatory C-mannosylation increase unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what structural or sequence features of individual TSRs determine whether a substrate requires B3GLCT for folding and secretion versus tolerating its loss.
  • No structural model of TSR discrimination
  • Full substrate repertoire and ranking of sensitivities incomplete
  • Mechanistic link from substrate-specific failure to specific Peters Plus features not fully defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
POFUT2

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 B3GALTL (B3GLCT) encodes a beta-1,3-galactosyltransferase-like glycosyltransferase; biallelic truncating mutations cause Peters Plus syndrome, placing it on the list of congenital malformation syndromes caused by glycosylation defects. Array-based comparative genomic hybridization (aCGH) and mutation analysis identifying biallelic truncating mutations in 20/20 patients American journal of human genetics Medium 16909395
2017 B3GLCT (b3glct in zebrafish) catalyzes the transfer of glucose via a β1-3 glycosidic linkage to O-linked fucose on thrombospondin type 1 repeats (TSRs); this enzymatic activity is conserved between zebrafish and human B3GLCT. In vitro glucosylation assay using embryo extracts transferring glucose from UDP-glucose to an O-fucosylated TSR substrate; TALEN-generated knockouts showed complete loss of this activity in double homozygous mutants PloS one High 28926587
2019 B3GLCT works sequentially with Protein O-fucosyltransferase 2 (POFUT2) to add an O-linked glucose β1-3 fucose disaccharide to properly folded thrombospondin type 1 repeats (TSRs); B3GLCT-mediated extension to the disaccharide is essential for only a subset of POFUT2 targets, with ADAMTS20 being highly sensitive and ADAMTS9 partially sensitive to B3GLCT loss. Mouse B3glct knockout models (two alleles); genetic epistasis combined with biochemical analysis of ADAMTS9 and ADAMTS20 secretion and function; rescue/interaction experiments Human molecular genetics High 31600785
2021 B3GLCT adds glucose to O-linked fucose on TSRs in the endoplasmic reticulum; loss of B3GLCT reduces secretion of SCO-spondin (SSPO) in cultured cells and causes intracellular accumulation with increased BiP levels, indicating a folding/quality control defect. TSRs of SSPO were confirmed to be modified with O-linked glucose-fucose by B3GLCT. Cell culture secretion assays with B3glct mutant cells; glycosylation analysis of SSPO TSRs; BiP co-localization; mRNA expression analysis of ADAMTS substrates in ependymal cells and subcommissural organ Glycobiology High 33909046
2021 Loss of B3GLCT in RPE cells abolishes glucose-β1,3-fucose modification on thrombospondin 1 (TSP1) TSR domains (confirmed by glycopeptide analysis), and increases C-mannosylation on TSR domains 1 and 3, but does not impair TSP1 secretion. B3GLCT knockout RPE cells generated by gene editing; glycopeptide mass spectrometry analysis of TSP1 modifications; secretion assays in KO vs. wildtype cells including TNFα stimulation and HEK293T overexpression Experimental eye research High 34695439
2013 A c.597-2A>G splice site mutation in B3GALTL causes complete skipping of exon 8, altering the open reading frame, generating a premature termination codon in exon 9, and triggering nonsense-mediated mRNA decay (NMD). Ex vivo mRNA analysis of patient-derived cells; RT-PCR demonstrating exon skipping; bioinformatics prediction of NMD Gene Medium 23954224
2021 Loss of B3GLCT in mouse ependymal cells results in fewer cilia basal bodies and altered translational polarity, with reduced ADAMTS9 and ADAMTS20 mRNA localization contributing to these ependymal abnormalities; this implicates B3GLCT substrates in cilia organization relevant to CSF flow. Mouse B3glct knockout; immunofluorescence and imaging of ependymal cilia basal bodies and translational polarity; in situ hybridization for substrate mRNAs Glycobiology Medium 33909046

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. American journal of human genetics 142 16909395
2008 Mutation analysis of B3GALTL in Peters Plus syndrome. American journal of medical genetics. Part A 50 18798333
2013 Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes. Clinical genetics 39 23889335
2019 ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome. Human molecular genetics 25 31600785
2012 Hydrocephalus, agenesis of the corpus callosum, and cleft lip/palate represent frequent associations in fetuses with Peters' plus syndrome and B3GALTL mutations. Fetal PPS phenotypes, expanded by Dandy Walker cyst and encephalocele. Prenatal diagnosis 21 23161355
2010 A novel nonsense B3GALTL mutation confirms Peters plus syndrome in a patient with multiple malformations and Peters anomaly. Ophthalmic genetics 20 21067481
2021 Hydrocephalus in mouse B3glct mutants is likely caused by defects in multiple B3GLCT substrates in ependymal cells and subcommissural organ. Glycobiology 14 33909046
2017 Functional characterization of zebrafish orthologs of the human Beta 3-Glucosyltransferase B3GLCT gene mutated in Peters Plus Syndrome. PloS one 11 28926587
2021 High-Throughput miRFluR Platform Identifies miRNA Regulating B3GLCT That Predict Peters' Plus Syndrome Phenotype, Supporting the miRNA Proxy Hypothesis. ACS chemical biology 8 34085516
2012 Two Tunisian patients with Peters plus syndrome harbouring a novel splice site mutation in the B3GALTL gene that modulates the mRNA secondary structure. Gene 7 22759511
2006 Murine ortholog of the novel glycosyltransferase, B3GTL: primary structure, characterization of the gene and transcripts, and expression in tissues. DNA and cell biology 7 16907644
2013 First functional analysis of a novel splicing mutation in the B3GALTL gene by an ex vivo approach in Tunisian patients with typical Peters plus syndrome. Gene 6 23954224
2021 Loss of the AMD-associated B3GLCT gene affects glycosylation of TSP1 without impairing secretion in retinal pigment epithelial cells. Experimental eye research 2 34695439
2020 Peters plus syndrome and Chorioretinal findings associated with B3GLCT gene mutation - a case report. BMC ophthalmology 2 32204707
2019 Contribution of a Novel B3GLCT Variant to Peters Plus Syndrome Discovered by a Combination of Next-Generation Sequencing and Automated Text Mining. International journal of molecular sciences 2 31795264
2013 An Unusual Case of Peters Plus Syndrome with Sexual Ambiguity and Absence of Mutations in the B3GALTL Gene. Iranian journal of pediatrics 2 24427506

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