GBGT1

Summary

GBGT1 (globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 (FORS blood group), HGNC:20460) is a protein-coding gene on chromosome 9q34.2, encoding Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 (Q8N5D6). Has lost the ability to synthesize Forssman glycolipid antigen (FORS1/FG).

This gene encodes a glycosyltransferase that plays a role in the synthesis of Forssman glycolipid (FG), a member of the globoseries glycolipid family. Glycolipids such as FG form attachment sites for the binding of pathogens to cells; expression of this protein may determine host tropism to microorganisms. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26301 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 77 total — 1 pathogenic
• MANE Select transcript: NM_021996

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20460
Approved symbol	GBGT1
Name	globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 (FORS blood group)
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Aliases	UDP-GalNAc, A3GALNT, MGC44848, FS
Ensembl gene	ENSG00000148288
Ensembl biotype	protein_coding
OMIM	606074
Entrez	26301

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000372036, ENST00000372038, ENST00000372040, ENST00000372043, ENST00000470431, ENST00000472281, ENST00000487864, ENST00000540636, ENST00000642916, ENST00000644196, ENST00000645973, ENST00000646215, ENST00000900748, ENST00000900749, ENST00000900750, ENST00000900751, ENST00000913413, ENST00000913414, ENST00000913415, ENST00000953293, ENST00000953294, ENST00000953295, ENST00000953296, ENST00000953297, ENST00000953298, ENST00000953299, ENST00000953300, ENST00000953301, ENST00000953302, ENST00000953303, ENST00000953304, ENST00000953305

RefSeq mRNA: 5 — MANE Select: NM_021996 NM_001282629, NM_001282632, NM_001288572, NM_001288573, NM_021996

CCDS: CCDS65175, CCDS65176, CCDS6960

Canonical transcript exons

ENST00000372040 — 7 exons

Exon	Start	End
ENSE00002215040	133152948	133154261
ENSE00003468855	133155901	133155936
ENSE00003550334	133162342	133162532
ENSE00003642386	133155178	133155312
ENSE00003667465	133161467	133161532
ENSE00003684805	133156015	133156065
ENSE00003814885	133163754	133163914

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 88.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0089 / max 101.5805, expressed in 1254 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102965	3.9357	1147
102966	1.0732	511

Top tissues by expression

241 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of stomach	UBERON:0001161	88.72	gold quality
monocyte	CL:0000576	87.94	gold quality
leukocyte	CL:0000738	87.57	gold quality
blood	UBERON:0000178	87.51	gold quality
stomach	UBERON:0000945	85.79	gold quality
right ovary	UBERON:0002118	85.09	gold quality
left ovary	UBERON:0002119	85.05	gold quality
granulocyte	CL:0000094	84.98	gold quality
right adrenal gland	UBERON:0001233	84.56	gold quality
right adrenal gland cortex	UBERON:0035827	84.52	gold quality
apex of heart	UBERON:0002098	83.54	gold quality
left adrenal gland	UBERON:0001234	83.40	gold quality
left adrenal gland cortex	UBERON:0035825	83.14	gold quality
vermiform appendix	UBERON:0001154	82.29	gold quality
adrenal cortex	UBERON:0001235	82.02	gold quality
fundus of stomach	UBERON:0001160	81.81	gold quality
omental fat pad	UBERON:0010414	81.63	gold quality
peritoneum	UBERON:0002358	81.57	gold quality
pancreatic ductal cell	CL:0002079	81.35	silver quality
adrenal gland	UBERON:0002369	81.22	gold quality
germinal epithelium of ovary	UBERON:0001304	81.12	gold quality
placenta	UBERON:0001987	80.97	gold quality
ileal mucosa	UBERON:0000331	80.94	silver quality
adipose tissue of abdominal region	UBERON:0007808	80.80	gold quality
upper lobe of left lung	UBERON:0008952	80.71	gold quality
upper lobe of lung	UBERON:0008948	80.70	gold quality
left uterine tube	UBERON:0001303	80.69	gold quality
ovary	UBERON:0000992	80.21	gold quality
right lobe of thyroid gland	UBERON:0001119	79.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	79.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.51
E-MTAB-7303	no	2.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting GBGT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-4693-5P	97.35	67.02	1234
HSA-MIR-4513	95.04	67.06	727
HSA-MIR-6855-3P	95.04	66.57	725

Literature-anchored findings (GeneRIF, showing 4)

• The Fs synthase gene, GBGT1, in A(pae) individuals encoded an arginine to glutamine change at residue 296. (PMID:23255552)
• GBGT1 expression is epigenetically silenced through promoter hypermethylation in ovarian cancer. (PMID:25294702)
• an amino acid substitution at codon 69 from methionine to threonine or serine (Met69Thr/Ser) modified enzymatic specificity of Blood group A/B glycosyltransferases and permitted FORS1 biosynthesis (PMID:29898878)
• extended the knowledge of GBGT1 variants, allele frequencies, and the characteristics of naturally occurring antibodies in our newest carbohydrate blood group system, FORS. The finding of c.363C>A-homozygous donors indicates that GBGT1 is dispensable. (PMID:30277576)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	gbgt1l9	ENSDARG00000011283
danio_rerio	gbgt1l5	ENSDARG00000019207
danio_rerio	gbgt1l1	ENSDARG00000025275
danio_rerio	gbgt1l3	ENSDARG00000035555
danio_rerio	gbgt1l4	ENSDARG00000068503
danio_rerio	gbgt1l7	ENSDARG00000091936
danio_rerio	gbgt1l8	ENSDARG00000091944
danio_rerio	gbgt1l6	ENSDARG00000091969
danio_rerio	gbgt1l2	ENSDARG00000092718
mus_musculus	Gbgt1	ENSMUSG00000026829

Paralogs (3): ABO (ENSG00000175164), A3GALT2 (ENSG00000184389), GLT6D1 (ENSG00000204007)

Protein

Protein identifiers

Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 — Q8N5D6 (reviewed: Q8N5D6)

Alternative names: Forssman glycolipid synthase-like protein

All UniProt accessions (7): Q8N5D6, A0A2R8Y4A7, A0A2R8YGC1, J7PW20, J7Q0Z1, Q5T7U8, Q5T7V0

UniProt curated annotations — full annotation on UniProt →

Function. Has lost the ability to synthesize Forssman glycolipid antigen (FORS1/FG). Might have acquired an alternative function in glycosphingolipid metabolism, but it remains to be established. It appears to have drifted more slowly than confirmed pseudogenes in the glycosyltransferase 6 family, suggesting that it has remained under evolutionary pressure.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Widely expressed. Expressed at higher level in placenta, ovary and peripheral blood leukocyte, whereas it is weakly expressed in liver, thymus, and testis. Expressed in bone marrow erythroid cells.

Cofactor. Binds 1 Mn(2+) ion per subunit.

Domain organisation. The conserved DXD motif is involved in cofactor binding. The manganese ion interacts with the beta-phosphate group of UDP and may also have a role in catalysis.

Pathway. Protein modification; protein glycosylation.

Polymorphism. Common alleles GBGT101N.01 and GBGT101N.02 do not synthesize Forssman glycolipid antigen (FORS1). A rare allele encoding an arginine to glutamine change at residue 296 is associated with the ability to synthesize Forssman antigen, which is expressed in erythrocytes and is inheritable, thus defining a new histo-blood group FORS, also known as Apae. This variation might have arised as a consequence of the selective pressure exerted by microorganisms. For instance, the uropathogenic E.coli expressing prsG adhesin only binds and agglutinates FORS1-expressing erythrocytes. Thus, FORS1-positive individuals might be more susceptible to certain pathogens.

Similarity. Belongs to the glycosyltransferase 6 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N5D6-1	1	yes
Q8N5D6-2	2
Q8N5D6-3	3

RefSeq proteins (5): NP_001269558, NP_001269561, NP_001275501, NP_001275502, NP_068836* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005076	Glyco_trans_6	Family
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily

Pfam: PF03414

Enzyme classification (BRENDA):

• EC 2.4.1.88 — globoside alpha-N-acetylgalactosaminyltransferase (BRENDA: 6 organisms, 21 substrates, 33 inhibitors, 5 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLOBOSIDE	0.0016–0.5	3
UDP-N-ACETYLGALACTOSAMINE	0.01–0.1	2

UniProt features (25 total): sequence variant 9, binding site 5, sequence conflict 3, topological domain 2, splice variant 2, chain 1, glycosylation site 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N5D6-F1	86.39	0.67

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 298 (nucleophile)

Ligand- & substrate-binding residues (5): 116–121; 206–208; 206; 208; 228–231

Glycosylation sites (1): 108

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 60 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GTGCCTT_MIR506, KEGG_GLYCOSPHINGOLIPID_BIOSYNTHESIS_GLOBO_SERIES, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_LIPOSACCHARIDE_METABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_METABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_BIOSYNTHETIC_PROCESS, GOMF_ACETYLGALACTOSAMINYLTRANSFERASE_ACTIVITY, GOMF_HEXOSYLTRANSFERASE_ACTIVITY, GOMF_GLYCOSYLTRANSFERASE_ACTIVITY

GO Biological Process (3): carbohydrate metabolic process (GO:0005975), glycolipid biosynthetic process (GO:0009247), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (5): metal ion binding (GO:0046872), globoside alpha-N-acetylgalactosaminyltransferase activity (GO:0047277), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hexosyltransferase activity (GO:0016758)

GO Cellular Component (4): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), vesicle (GO:0031982), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
glycolipid metabolic process	1
lipid biosynthetic process	1
carbohydrate derivative biosynthetic process	1
cation binding	1
acetylgalactosaminyltransferase activity	1
catalytic activity	1
transferase activity	1
glycosyltransferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

480 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GBGT1	B3GALNT1	O75752	610
GBGT1	A4GALT	Q9NPC4	507
GBGT1	MED13L	Q71F56	390
GBGT1	SUMF1	Q8NBK3	380
GBGT1	C22orf42	Q6IC83	377
GBGT1	FUT3	P21217	372
GBGT1	DOK2	O60496	370
GBGT1	FUT7	Q11130	356
GBGT1	FUT1	P19526	350
GBGT1	ENTHD1	Q8IYW4	348
GBGT1	B3GALT2	O43825	348
GBGT1	B3GALT5	Q9Y2C3	348
GBGT1	ST3GAL6	Q9Y274	324
GBGT1	FUT2	Q10981	323
GBGT1	B3GALT1	Q9Y5Z6	323

IntAct

2 interactions, top by confidence:

A	B	Type	Score
GBGT1	dppD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (1): GLT6D1 (Negative Genetic)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A4D0V7, C5H5C4, F6Q1T7, O70309, O75354, P17405, P18084, P18424, P22413, P50747, P52850, P58242, P61642, P80747, Q04519, Q0VBD0, Q0VD19, Q13219, Q52KP5, Q58CQ9, Q5QQ51, Q5STE3, Q64687, Q6DFZ6, Q6KFX9, Q6MZW2, Q6P988, Q6UWX4, Q6YGZ1, Q6ZXD2, Q71RP1, Q812F8, Q8BJQ9, Q8C1F4, Q8C419, Q8N5D6, Q8N6G5, Q8R116

Diamond homologs: A0A4Z3, A1YGR5, A1YGR6, A2AUQ7, D3ZNQ3, G3V9Q9, P14769, P16442, P23336, P38649, P50127, Q2NKH9, Q2YDM8, Q3L7M0, Q3V1N9, Q4R5T7, Q5ZLK4, Q7Z4J2, Q8CFC4, Q8HY56, Q8HYB2, Q8N5D6, Q8SPR2, Q8SQ20, Q8VI38, Q95158, Q9ET32, U3KPV4, Q4G0N0, Q5JBG6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

77 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	58
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4075962	GRCh37/hg19 9q33.2-34.3(chr9:124095694-141020389)x3	Pathogenic

SpliceAI

1570 predictions. Top by Δscore:

Variant	Effect	Δscore
9:133155176:A:AC	donor_gain	1.0000
9:133155177:C:CC	donor_gain	1.0000
9:133155179:T:TA	donor_gain	1.0000
9:133161465:A:AC	donor_gain	1.0000
9:133161466:C:CC	donor_gain	1.0000
9:133163752:ACT:A	donor_gain	1.0000
9:133163753:CTC:C	donor_gain	1.0000
9:133154243:C:CC	acceptor_gain	0.9900
9:133155176:ACTT:A	donor_gain	0.9900
9:133155177:CTT:C	donor_gain	0.9900
9:133155177:CTTC:C	donor_gain	0.9900
9:133155180:C:A	donor_gain	0.9900
9:133155283:C:CT	acceptor_gain	0.9900
9:133156061:TGTTG:T	acceptor_gain	0.9900
9:133156063:TTG:T	acceptor_gain	0.9900
9:133156064:TG:T	acceptor_gain	0.9900
9:133156066:C:CC	acceptor_gain	0.9900
9:133156073:C:CT	acceptor_gain	0.9900
9:133157502:AG:A	donor_gain	0.9900
9:133157549:TG:T	donor_gain	0.9900
9:133162943:G:C	donor_gain	0.9900
9:133162990:G:C	donor_gain	0.9900
9:133163752:A:AC	donor_gain	0.9900
9:133163753:C:CC	donor_gain	0.9900
9:133163753:CT:C	donor_gain	0.9900
9:133155176:ACTTC:A	donor_gain	0.9800
9:133155177:CTTCC:C	donor_gain	0.9800
9:133155276:C:CT	acceptor_gain	0.9800
9:133155280:A:T	acceptor_gain	0.9800
9:133155896:CCTA:C	donor_loss	0.9800

AlphaMissense

2268 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:133155252:G:C	F95L	0.930
9:133155252:G:T	F95L	0.930
9:133155254:A:G	F95L	0.930
9:133153847:G:C	F258L	0.925
9:133153847:G:T	F258L	0.925
9:133153849:A:G	F258L	0.925
9:133153988:A:C	F211L	0.909
9:133153988:A:T	F211L	0.909
9:133153990:A:G	F211L	0.909
9:133154012:G:C	F203L	0.876
9:133154012:G:T	F203L	0.876
9:133154014:A:G	F203L	0.876
9:133154216:G:C	F135L	0.872
9:133154216:G:T	F135L	0.872
9:133154218:A:G	F135L	0.872
9:133153871:A:C	F250L	0.867
9:133153871:A:T	F250L	0.867
9:133153873:A:G	F250L	0.867
9:133153826:G:C	F265L	0.854
9:133153826:G:T	F265L	0.854
9:133153828:A:G	F265L	0.854
9:133153989:A:G	F211S	0.845
9:133154237:G:C	F128L	0.844
9:133154237:G:T	F128L	0.844
9:133154239:A:G	F128L	0.844
9:133153669:A:G	Y318H	0.841
9:133154180:G:C	F147L	0.841
9:133154180:G:T	F147L	0.841
9:133154182:A:G	F147L	0.841
9:133153694:C:A	K309N	0.839

dbSNP variants (sampled 300 via entrez): RS1000260653 (9:133156533 G>A), RS1000296669 (9:133152567 G>T), RS1000333933 (9:133156410 C>T), RS1000357839 (9:133157724 C>T), RS1000412334 (9:133152904 G>A,C), RS1000821196 (9:133163279 G>A,C), RS1000888622 (9:133161994 G>A,T), RS1000896882 (9:133161949 C>G), RS1000961512 (9:133156629 C>T), RS1001115320 (9:133161671 G>A), RS1001171353 (9:133163072 C>A), RS1001212207 (9:133156608 C>T), RS1001548734 (9:133164605 T>C), RS1001770956 (9:133164355 C>G), RS1001807227 (9:133156897 G>T)

Disease associations

OMIM: gene MIM:606074 | disease phenotypes: MIM:191100

GenCC curated gene-disease

Mondo (1): tuberous sclerosis 1 (MONDO:0008612)

Orphanet (1): Tuberous sclerosis complex (Orphanet:805)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_770	Metabolite levels	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010392	sphingomyelin 16:1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565346	Tuberous Sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Gallic Acid	increases expression	1
Lead	affects methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Vanadates	decreases expression	1
Lithium Chloride	increases expression	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation