Affinage

B3GLCT

Beta-1,3-glucosyltransferase · UniProt Q6Y288

Length
498 aa
Mass
56.6 kDa
Annotated
2026-04-28
16 papers in source corpus 6 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

B3GLCT is an endoplasmic reticulum-resident β1,3-glucosyltransferase that transfers glucose to O-linked fucose on thrombospondin type 1 repeats (TSRs), functioning sequentially with POFUT2 to generate a glucose-β1,3-fucose disaccharide that stabilizes TSR folding and promotes secretion of TSR-containing proteins (PMID:28926587, PMID:31600785, PMID:33909046). Loss of B3GLCT differentially impairs secretion of ADAMTS superfamily members and SCO-spondin, with ADAMTS20 being highly sensitive and ADAMTS9 partially sensitive, whereas thrombospondin 1 secretion is unaffected despite loss of the disaccharide modification (PMID:31600785, PMID:34695439). B3GLCT inactivation triggers ER stress (elevated BiP), reduces ependymal cilia basal bodies, and causes hydrocephalus, eye abnormalities, and cleft palate in mouse models, recapitulating features of Peters Plus syndrome caused by biallelic loss-of-function mutations in humans (PMID:16909395, PMID:33909046).

Mechanistic history

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

    Identifying B3GLCT as the gene mutated in Peters Plus syndrome established that a glycosyltransferase-like enzyme is essential for normal craniofacial and ocular development, but its enzymatic activity and substrate were unknown.

    Evidence Array-based CGH and mutation analysis in 20 patients with biallelic truncating mutations

    PMID:16909395

    Open questions at the time
    • Enzymatic activity not demonstrated — gene annotated only by homology
    • Substrate and acceptor sugar unknown
    • No animal model to dissect developmental phenotypes
  2. 2013 Medium

    Demonstrating that a common splice-site mutation triggers nonsense-mediated mRNA decay clarified the molecular mechanism of allele loss but did not address enzyme function.

    Evidence Ex vivo mRNA splicing analysis and cDNA sequencing of c.597-2A>G variant

    PMID:23954224

    Open questions at the time
    • Single lab study; not independently confirmed in additional patient cohorts
    • Protein-level consequence not directly measured
    • Genotype–phenotype correlation across mutation spectrum not addressed
  3. 2017 High

    In vitro glucosylation assays resolved B3GLCT's catalytic activity as a β1,3-glucosyltransferase that transfers glucose to O-fucosylated TSRs, correcting the earlier annotation as a galactosyltransferase.

    Evidence In vitro glucosylation with UDP-glucose and O-fucosylated TSR substrate using wildtype and TALEN-generated b3glct knockout zebrafish extracts

    PMID:28926587

    Open questions at the time
    • Structural basis for donor (UDP-glucose) and acceptor specificity unknown
    • Full repertoire of TSR-containing substrates not determined
    • Mammalian in vitro reconstitution not yet performed
  4. 2019 High

    Mouse knockouts revealed that B3GLCT acts sequentially with POFUT2 and that individual TSR-containing substrates differ in their dependence on glucosylation for secretion, linking specific substrate sensitivities (ADAMTS20, ADAMTS9) to discrete developmental defects.

    Evidence Mouse B3glct knockout models with genetic epistasis and biochemical secretion assays

    PMID:31600785

    Open questions at the time
    • Molecular basis for differential substrate sensitivity not defined
    • Whether other ADAMTS family members are affected remains untested
    • Direct structural evidence for glucose stabilizing TSR fold not available
  5. 2021 High

    B3GLCT loss was shown to impair SCO-spondin secretion, elevate ER chaperone BiP, and reduce ependymal cilia basal bodies, linking the glycosylation defect to ER stress, abnormal protein quality control, and hydrocephalus.

    Evidence Mouse B3glct knockout cultured cell secretion assays, BiP colocalization, cilia basal body quantification

    PMID:33909046

    Open questions at the time
    • Direct mechanism connecting TSR underglycosylation to cilia basal body loss not reconstituted
    • Contribution of ER stress versus substrate loss to developmental phenotypes not dissected
    • Whether BiP elevation reflects specific ERAD targeting of misfolded substrates is untested
  6. 2021 High

    Glycopeptide mass spectrometry confirmed B3GLCT-dependent glucose-β1,3-fucose on TSP1, but TSP1 secretion was unaffected, demonstrating that not all TSR-containing proteins require this modification for secretion and revealing compensatory increases in C-mannosylation.

    Evidence B3GLCT knockout RPE cells, glycopeptide MS, secretion assay

    PMID:34695439

    Open questions at the time
    • Functional consequence of increased C-mannosylation on TSP1 domains unknown
    • Whether TSP1 function (e.g., TGF-β activation) is affected despite normal secretion not tested
    • Systematic mapping of all affected versus unaffected substrates in vivo not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural determinants within TSRs that dictate dependence on B3GLCT-mediated glucosylation for folding and secretion remain undefined, as does the mechanism by which underglycosylated substrates are recognized and routed to ERAD versus secretion.
  • No crystal structure of B3GLCT or B3GLCT–TSR complex available
  • ERAD pathway for misfolded TSR substrates not identified
  • Comprehensive substrate catalogue across tissues and developmental stages lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 2 R-HSA-9609507 Protein localization 2
Partners
ADAMTS20ADAMTS9POFUT2SSPOTHBS1

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 B3GALTL (B3GLCT) encodes a putative β1,3-galactosyltransferase-like glycosyltransferase; loss-of-function mutations cause Peters Plus syndrome, placing B3GLCT on the list of congenital malformation syndromes caused by glycosylation defects. Array-based comparative genomic hybridization, mutation analysis in 20 patients with biallelic truncating mutations American journal of human genetics High 16909395
2017 B3GLCT catalyzes the transfer of glucose via a β1-3 glycosidic linkage to O-linked fucose on thrombospondin type 1 repeats (TSRs); in vitro glucosylation assays using UDP-glucose and O-fucosylated TSR substrate confirmed this enzymatic activity is conserved in vertebrates. In vitro glucosylation assay with wildtype and b3glct knockout zebrafish embryo extracts; TALEN-mediated knockout demonstrating complete loss of activity PloS one High 28926587
2019 B3GLCT works sequentially with POFUT2 to add an O-linked glucose-β1-3-fucose disaccharide to TSRs; B3GLCT inactivation differentially affects ADAMTS superfamily substrates, with ADAMTS20 being highly sensitive and ADAMTS9 partially sensitive, linking specific substrate loss to distinct developmental defects (hydrocephalus/white spotting from ADAMTS20 loss; eye abnormalities from partial ADAMTS9 reduction; cleft palate from combined loss). Mouse B3glct knockout models, genetic epistasis, biochemical secretion assays Human molecular genetics High 31600785
2021 B3GLCT adds glucose to O-linked fucose on TSRs in the endoplasmic reticulum, stabilizing the TSR fold and promoting secretion; loss of B3GLCT reduces secretion of SCO-spondin (SSPO) in cultured cells, increases intracellular BiP levels indicating a folding defect, and results in secreted SSPO colocalizing with BiP, suggesting abnormal extracellular assembly. Cultured cell secretion assays with B3glct mutant mouse model, immunofluorescence, BiP co-localization, in situ hybridization Glycobiology High 33909046
2021 Loss of B3GLCT in mouse B3glct mutants causes ependymal cell abnormalities including fewer cilia basal bodies and altered translational polarity, contributing to hydrocephalus; this implicates B3GLCT-mediated TSR glycosylation in ependymal cell ciliogenesis. Mouse B3glct knockout, cilia basal body quantification, immunofluorescence, mRNA localization Glycobiology Medium 33909046
2021 B3GLCT-mediated glucose-β1,3-fucose modification was confirmed on thrombospondin 1 (TSP1) in retinal pigment epithelial cells by glycopeptide analysis; loss of B3GLCT in RPE knockout cells abolished this modification but did not affect TSP1 secretion, and increased C-mannosylation on TSR domains 1 and 3. B3GLCT knockout RPE cells, glycopeptide mass spectrometry analysis, secretion assay, 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 and generating a premature termination codon in exon 9, which triggers nonsense-mediated mRNA decay (NMD). Ex vivo mRNA splicing analysis, cDNA sequencing, bioinformatics splice prediction Gene Medium 23954224

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 13 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