HS3ST4

Summary

HS3ST4 (heparan sulfate-glucosamine 3-sulfotransferase 4, HGNC:5200) is a protein-coding gene on chromosome 16p12.1, encoding Heparan sulfate glucosamine 3-O-sulfotransferase 4 (Q9Y661). Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate.

This gene encodes the enzyme heparan sulfate D-glucosaminyl 3-O-sulfotransferase 4. This enzyme generates 3-O-sulfated glucosaminyl residues in heparan sulfate. Cell surface heparan sulfate is used as a receptor by herpes simplex virus type 1 (HSV-1), and expression of this gene is thought to play a role in HSV-1 pathogenesis.

Source: NCBI Gene 9951 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_006040

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5200
Approved symbol	HS3ST4
Name	heparan sulfate-glucosamine 3-sulfotransferase 4
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Aliases	3OST4
Ensembl gene	ENSG00000182601
Ensembl biotype	protein_coding
OMIM	604059
Entrez	9951

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000331351, ENST00000475436

RefSeq mRNA: 1 — MANE Select: NM_006040 NM_006040

CCDS: CCDS53995

Canonical transcript exons

ENST00000331351 — 2 exons

Exon	Start	End
ENSE00001299178	26135612	26137685
ENSE00001318483	25691959	25693151

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 96.17.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7215 / max 54.0875, expressed in 206 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153276	0.7215	206

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.17	gold quality
postcentral gyrus	UBERON:0002581	89.27	gold quality
endothelial cell	CL:0000115	89.23	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.63	gold quality
entorhinal cortex	UBERON:0002728	87.25	gold quality
superior frontal gyrus	UBERON:0002661	87.07	gold quality
parietal lobe	UBERON:0001872	85.94	gold quality
prefrontal cortex	UBERON:0000451	85.69	gold quality
frontal cortex	UBERON:0001870	85.01	gold quality
neocortex	UBERON:0001950	84.43	gold quality
pancreatic ductal cell	CL:0002079	84.31	silver quality
right frontal lobe	UBERON:0002810	83.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.92	gold quality
cerebral cortex	UBERON:0000956	83.86	gold quality
primary visual cortex	UBERON:0002436	83.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.12	gold quality
anterior cingulate cortex	UBERON:0009835	82.59	gold quality
middle temporal gyrus	UBERON:0002771	82.13	gold quality
Ammon’s horn	UBERON:0001954	81.57	gold quality
Brodmann (1909) area 23	UBERON:0013554	81.28	gold quality
occipital lobe	UBERON:0002021	79.85	gold quality
pons	UBERON:0000988	79.65	gold quality
temporal lobe	UBERON:0001871	78.43	gold quality
caudate nucleus	UBERON:0001873	77.43	gold quality
forebrain	UBERON:0001890	76.17	gold quality
hypothalamus	UBERON:0001898	75.91	gold quality
brain	UBERON:0000955	75.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	74.71	gold quality
amygdala	UBERON:0001876	74.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.10	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2685.71
E-HCAD-30	yes	2355.21
E-HCAD-35	yes	2138.50
E-HCAD-25	yes	1213.79
E-ANND-3	yes	3.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting HS3ST4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-646	99.68	67.84	1645

Literature-anchored findings (GeneRIF, showing 4)

• 3-OST-2 and 3-OST-4 are the major neural gD-type 3-OSTs, and so are prime candidates for participating in HS-dependent neurobiologic events. (PMID:17482450)
• The 3OST-2 and -4 are specifically expressed in brain. (PMID:18757372)
• This study provided that additional genome-wide associations, near HS3ST4 were identified and other putative modulators of memory performance were revealed by a pathway approach and hippocampal gene expression analyses. (PMID:25648963)
• Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity. (PMID:34904858)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hs3st4	ENSDARG00000052648
mus_musculus	Hs3st4	ENSMUSG00000078591
rattus_norvegicus	Hs3st4	ENSRNOG00000063290
drosophila_melanogaster	sfl	FBGN0020251
caenorhabditis_elegans		WBGENE00002028

Paralogs (10): HS3ST1 (ENSG00000002587), NDST1 (ENSG00000070614), HS3ST2 (ENSG00000122254), HS3ST3B1 (ENSG00000125430), NDST4 (ENSG00000138653), HS3ST3A1 (ENSG00000153976), HS3ST6 (ENSG00000162040), NDST3 (ENSG00000164100), NDST2 (ENSG00000166507), HS3ST5 (ENSG00000249853)

Protein

Protein identifiers

Heparan sulfate glucosamine 3-O-sulfotransferase 4 — Q9Y661 (reviewed: Q9Y661)

Alternative names: Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 4

All UniProt accessions (1): Q9Y661

UniProt curated annotations — full annotation on UniProt →

Function. Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate. Unlike 3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Brain-specific.

Similarity. Belongs to the sulfotransferase 1 family.

RefSeq proteins (1): NP_006031* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000863	Sulfotransferase_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037359	NST/OST	Family

Pfam: PF00685

Enzyme classification (BRENDA):

• EC 2.8.2.23 — [heparan sulfate]-glucosamine 3-sulfotransferase 1 (BRENDA: 5 organisms, 26 substrates, 5 inhibitors, 3 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
3’-PHOSPHOADENOSINE 5’-PHOSPHOSULFATE	0.01	1
GLCNSO3(6-OSO3)-GLCA-GLCNSO3(6-OSO3)-IDOA(2-OSO3	0.006	1

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + 3’-phosphoadenylyl sulfate = 3-sulfo-alpha-D-glucosaminyl-heparan sulfate + adenosine 3’,5’-bisphosphate + H(+) (RHEA:15461)

UniProt features (24 total): binding site 7, glycosylation site 4, region of interest 3, compositionally biased region 3, topological domain 2, chain 1, transmembrane region 1, disulfide bond 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y661-F1	75.96	0.55

Functional residue map

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

Ligand- & substrate-binding residues (7): 207–211; 229–235; 260–263; 288; 296; 328–329; 413–417

Disulfide bonds (1): 396–408

Glycosylation sites (4): 105, 178, 318, 389

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis

MSigDB gene sets: 90 (showing top): BENPORATH_ES_WITH_H3K27ME3, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, AP4_Q6, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GATA1_04, TATA_C, AACTTT_UNKNOWN, FREAC4_01, POU3F2_02, CCCNNGGGAR_OLF1_01

GO Biological Process (2): heparan sulfate proteoglycan biosynthetic process (GO:0015012), heparan sulfate proteoglycan metabolic process (GO:0030201)

GO Molecular Function (3): [heparan sulfate]-glucosamine 3-sulfotransferase activity (GO:0008467), sulfotransferase activity (GO:0008146), transferase activity (GO:0016740)

GO Cellular Component (3): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
proteoglycan metabolic process	1
heparan sulfate sulfotransferase activity	1
transferase activity, transferring sulphur-containing groups	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HS3ST4	SULT1C3	Q6IMI6	725
HS3ST4	SULT1C4	O75897	717
HS3ST4	SULT1B1	O43704	683
HS3ST4	HS2ST1	Q7LGA3	667
HS3ST4	HS6ST1	O60243	591
HS3ST4	GLCE	O94923	574
HS3ST4	HS6ST2	Q96MM7	547
HS3ST4	HS6ST3	Q8IZP7	543
HS3ST4	UST	Q9Y2C2	532
HS3ST4	CHST12	Q9NRB3	512
HS3ST4	K7EP71	K7EP71	491
HS3ST4	SULF2	Q8IWU5	435
HS3ST4	NRP1	O14786	420
HS3ST4	GSG1L	Q6UXU4	417
HS3ST4	EXT1	Q16394	403

IntAct

2 interactions, top by confidence:

A	B	Type	Score
HS3ST4	IPO13	psi-mi:“MI:0914”(association)	0.350
DOCK3	HS6ST3	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): SLC25A14 (Affinity Capture-MS), INTS7 (Affinity Capture-MS), DCP1B (Affinity Capture-MS), SKI (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), SMEK2 (Affinity Capture-MS), HS3ST2 (Affinity Capture-MS), PPTC7 (Affinity Capture-MS), IPO13 (Affinity Capture-MS), HS3ST4 (Affinity Capture-MS), ATP12A (Affinity Capture-MS)

ESM2 similar proteins: A2BGL3, A4D0V7, A4FUW8, D4PHA7, O43916, O88199, O93403, Q2TBF2, Q505J3, Q58CX7, Q5DTK1, Q5NDE9, Q5NDF0, Q5NDF1, Q5NDF2, Q5RJQ0, Q658N2, Q68CR1, Q6DBY9, Q6L8S8, Q6L9W6, Q6XQG8, Q70JA7, Q7LFX5, Q7LGC8, Q80TS8, Q80WV3, Q80XH4, Q8BW41, Q8C3I9, Q8CHI9, Q8K2W3, Q8NAT1, Q8NCG5, Q91XQ5, Q92179, Q99LL3, Q9BXP8, Q9EP78, Q9EQC0

Diamond homologs: O14792, O35310, O95803, O97583, Q5GFD5, Q673U1, Q80W66, Q8BKN6, Q8BSL4, Q8IZT8, Q96QI5, Q9EQW8, Q9ESG5, Q9H3R1, Q9QZS6, Q9Y278, Q9Y661, Q9Y662, Q9Y663, P52849, Q60V90, Q966W3, Q9EQH7, Q9V3L1, P52848, P52850, Q02353, Q3UHN9, Q5U4X8, Q6GQK9, Q55GK8, Q91XQ5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3227 predictions. Top by Δscore:

Variant	Effect	Δscore
16:25721779:A:T	donor_gain	1.0000
16:25781263:TTTA:T	donor_gain	1.0000
16:25786966:G:GT	donor_gain	1.0000
16:25889271:G:GT	donor_gain	1.0000
16:26135608:CTAG:C	acceptor_loss	1.0000
16:26135609:TA:T	acceptor_loss	1.0000
16:26135610:A:AG	acceptor_gain	1.0000
16:26135610:A:T	acceptor_loss	1.0000
16:26135611:G:GC	acceptor_gain	1.0000
16:26135611:GA:G	acceptor_gain	1.0000
16:26135611:GAA:G	acceptor_gain	1.0000
16:26135611:GAAA:G	acceptor_gain	1.0000
16:26135611:GAAAT:G	acceptor_gain	1.0000
16:25693122:GAAC:G	donor_gain	0.9900
16:25721778:G:T	donor_gain	0.9900
16:25781262:GTT:G	donor_gain	0.9900
16:25781269:G:GG	donor_gain	0.9900
16:25802183:G:T	donor_gain	0.9900
16:26074313:C:CA	acceptor_gain	0.9900
16:25693147:TACAG:T	donor_loss	0.9800
16:25693148:ACAG:A	donor_loss	0.9800
16:25693149:CAGGT:C	donor_loss	0.9800
16:25693150:AGGTA:A	donor_loss	0.9800
16:25693152:GTA:G	donor_loss	0.9800
16:25693153:T:G	donor_loss	0.9800
16:25770307:A:G	donor_gain	0.9800
16:25781264:TTAA:T	donor_gain	0.9800
16:25814872:G:GT	donor_gain	0.9800
16:25825043:A:G	acceptor_gain	0.9800
16:25889325:A:T	donor_gain	0.9800

AlphaMissense

2957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:25693027:G:A	G204R	1.000
16:25693027:G:C	G204R	1.000
16:25693027:G:T	G204W	1.000
16:25693028:G:A	G204E	1.000
16:25693028:G:T	G204V	1.000
16:25693035:G:C	K206N	1.000
16:25693035:G:T	K206N	1.000
16:25693036:A:C	K207Q	1.000
16:25693036:A:G	K207E	1.000
16:25693037:A:T	K207I	1.000
16:25693038:A:C	K207N	1.000
16:25693038:A:T	K207N	1.000
16:25693039:G:A	G208R	1.000
16:25693039:G:C	G208R	1.000
16:25693040:G:A	G208E	1.000
16:25693042:G:A	G209R	1.000
16:25693042:G:C	G209R	1.000
16:25693042:G:T	G209W	1.000
16:25693043:G:A	G209E	1.000
16:25693043:G:T	G209V	1.000
16:25693046:C:T	T210I	1.000
16:25693049:G:C	R211P	1.000
16:25693055:T:C	L213P	1.000
16:25693058:T:C	L214P	1.000
16:25693085:T:A	V223E	1.000
16:25693102:G:A	E229K	1.000
16:25693104:G:C	E229D	1.000
16:25693104:G:T	E229D	1.000
16:25693108:C:G	H231D	1.000
16:25693111:T:C	F232L	1.000

dbSNP variants (sampled 300 via entrez): RS1000005408 (16:25716310 T>C), RS1000009702 (16:25743068 G>A), RS1000015510 (16:26085804 A>T), RS1000028571 (16:26065346 C>G,T), RS1000033490 (16:25796221 G>A), RS1000035675 (16:25868327 A>G), RS1000041594 (16:25875592 T>A,C,G), RS1000041707 (16:26128541 G>A,C), RS1000047704 (16:25756160 A>G), RS1000050683 (16:25752761 G>C), RS1000052627 (16:25830772 A>C,G), RS1000057801 (16:25746942 G>A,C), RS1000062049 (16:25834141 T>A), RS1000073978 (16:25875866 A>C), RS1000077144 (16:25913887 A>G)

Disease associations

OMIM: gene MIM:604059 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001762_734	Obesity-related traits	7.000000e-06
GCST002701_1	Verbal declarative memory	3.000000e-08
GCST002701_16	Verbal declarative memory	1.000000e-07
GCST005051_28	Obstructive sleep apnea trait (apnea hypopnea index)	7.000000e-07
GCST005352_18	Paclitaxel disposition in epithelial ovarian cancer	3.000000e-06
GCST005359_23	Disease progression in age-related macular degeneration	2.000000e-07
GCST006110_33	Nose morphology	1.000000e-06
GCST007540_9	PEG-asparaginase hypersensitivity without enzyme activity in childhood acute lymphoblastic leukaemia	6.000000e-07
GCST007626_3	Lack of perseverance	6.000000e-07
GCST009261_12	Pallidum volume	9.000000e-06
GCST009268_5	Dental caries (decayed, missing and filled tooth surfaces)	2.000000e-07
GCST010396_65	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-06
GCST011385_5	Vaginal microbiome composition (Shannon diversity index)	9.000000e-07
GCST90007009_1	Gut microbiota relative abundance (Faecalibacterium)	8.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005106	body composition measurement
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0007817	sleep apnea measurement
EFO:0008336	disease progression measurement
EFO:0004881	asparaginase hypersensitivity
EFO:0006946	behavioural disinhibition measurement
EFO:0007874	gut microbiome measurement
EFO:0011013	vaginal microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4074471	HS3ST4		0.00	0
rs9933692	HS3ST4		0.00	0

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, increases expression	2
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Doxorubicin	increases expression	1
Methamphetamine	affects response to substance	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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