CHST3

Summary

CHST3 (carbohydrate sulfotransferase 3, HGNC:1971) is a protein-coding gene on chromosome 10q22.1, encoding Carbohydrate sulfotransferase 3 (Q7LGC8). Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin.

This gene encodes an enzyme which catalyzes the sulfation of chondroitin, a proteoglycan found in the extracellular matrix and most cells which is involved in cell migration and differentiation. Mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis.

Source: NCBI Gene 9469 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondyloepiphyseal dysplasia with congenital joint dislocations (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 476 total — 30 pathogenic, 23 likely-pathogenic (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 28 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 148
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.12 (unconstrained)
• MANE Select transcript: NM_004273

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1971
Approved symbol	CHST3
Name	carbohydrate sulfotransferase 3
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	C6ST, C6ST1
Ensembl gene	ENSG00000122863
Ensembl biotype	protein_coding
OMIM	603799
Entrez	9469

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000373115

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000373115, ENST00000879006, ENST00000943244, ENST00001116439, ENST00001123680, ENST00001127310, ENST00001142073

RefSeq mRNA: 3 — MANE Select: NM_004273 NM_001441201, NM_001441202, NM_004273

CCDS: CCDS7312

Canonical transcript exons

ENST00000373115 — 3 exons

Exon	Start	End
ENSE00001459536	72007172	72013558
ENSE00001459537	72005736	72005982
ENSE00001459538	71964395	71964694

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 96.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5410 / max 81.0053, expressed in 1356 samples.

Highest expression (Bgee): tibia, cartilage tissue, ventricular zone, coronary artery, popliteal artery.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CHST3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 28 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 29 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Colon Sigmoid	eqtl	3.0e-23	+0.40	10:72018849:G:C
Testis	eqtl	1.4e-20	-0.23	10:72012403:G:T
Cells Cultured fibroblasts	eqtl	5.7e-18	+0.16	10:72017934:T:A
Cells EBV-transformed lymphocytes	eqtl	9.1e-17	-0.65	10:71980855:G:A
Colon Transverse	eqtl	5.0e-13	+0.15	10:72012578:T:C
Minor Salivary Gland	eqtl	3.6e-10	-0.65	10:72038163:T:C
Muscle Skeletal	eqtl	1.2e-09	-0.25	10:72022661:C:T
Thyroid	eqtl	1.8e-07	-0.19	10:71982201:T:C
Esophagus Mucosa	eqtl	4.7e-07	+0.20	10:72009749:C:T
Prostate	eqtl	8.9e-07	+0.23	10:72009832:C:T
Small Intestine Terminal Ileum	eqtl	4.3e-06	+0.25	10:72009832:C:T
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-05	+0.34	10:72051760:G:A
Esophagus Muscularis	eqtl	2.5e-04	+0.13	10:72006237:A:G
Brain Caudate basal ganglia	eqtl	3.8e-04	-0.18	10:71985841:C:T
Brain Nucleus accumbens basal ganglia	eqtl	4.2e-04	-0.23	10:71981079:A:C
Brain Putamen basal ganglia	eqtl	5.2e-04	-0.22	10:71972907:T:C
Skin Sun Exposed Lower leg	eqtl	5.4e-04	+0.30	10:72051760:G:A
Artery Aorta	eqtl	6.4e-04	+0.14	10:72022264:A:T
Brain Cerebellar Hemisphere	eqtl	9.1e-04	-0.17	10:72146392:A:G
Uterus	eqtl	9.9e-04	+0.39	10:72057541:C:T

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
105468	3.4949	999
105467	3.1586	1218
105470	0.7456	419
105469	0.5935	365
105475	0.2926	146
105471	0.2557	117

Top tissues by expression

showing 100 of 284 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	96.05	gold quality
cartilage tissue	UBERON:0002418	91.53	gold quality
ventricular zone	UBERON:0003053	88.52	gold quality
right coronary artery	UBERON:0001625	87.90	gold quality
popliteal artery	UBERON:0002250	87.47	gold quality
tibial artery	UBERON:0007610	87.44	gold quality
descending thoracic aorta	UBERON:0002345	87.42	gold quality
decidua	UBERON:0002450	87.29	gold quality
aorta	UBERON:0000947	87.19	gold quality
thoracic aorta	UBERON:0001515	87.11	gold quality
ascending aorta	UBERON:0001496	87.06	gold quality
left coronary artery	UBERON:0001626	86.49	gold quality
right ovary	UBERON:0002118	85.85	gold quality
coronary artery	UBERON:0001621	85.54	gold quality
left ovary	UBERON:0002119	85.35	gold quality
stromal cell of endometrium	CL:0002255	85.22	gold quality
cranial nerve II	UBERON:0000941	84.90	gold quality
tibial nerve	UBERON:0001323	84.57	gold quality
left uterine tube	UBERON:0001303	83.81	gold quality
inferior olivary complex	UBERON:0002127	83.61	gold quality
gastrocnemius	UBERON:0001388	83.28	gold quality
right atrium auricular region	UBERON:0006631	83.23	gold quality
smooth muscle tissue	UBERON:0001135	82.89	gold quality
right adrenal gland	UBERON:0001233	82.88	gold quality
left adrenal gland	UBERON:0001234	82.84	gold quality
cardiac atrium	UBERON:0002081	82.84	gold quality
heart left ventricle	UBERON:0002084	82.81	gold quality
ovary	UBERON:0000992	82.80	gold quality
sural nerve	UBERON:0015488	82.75	gold quality
left adrenal gland cortex	UBERON:0035825	82.43	gold quality
cardiac ventricle	UBERON:0002082	82.35	gold quality
body of stomach	UBERON:0001161	82.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.24	gold quality
muscle of leg	UBERON:0001383	82.15	gold quality
heart	UBERON:0000948	82.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.02	gold quality
body of uterus	UBERON:0009853	82.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.01	gold quality
lower esophagus	UBERON:0013473	81.97	gold quality
right adrenal gland cortex	UBERON:0035827	81.90	gold quality
right testis	UBERON:0004534	81.68	gold quality
apex of heart	UBERON:0002098	81.60	gold quality
left testis	UBERON:0004533	81.21	gold quality
adrenal gland	UBERON:0002369	81.10	gold quality
omental fat pad	UBERON:0010414	81.10	gold quality
peritoneum	UBERON:0002358	81.06	gold quality
adrenal cortex	UBERON:0001235	81.01	gold quality
mucosa of stomach	UBERON:0001199	80.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.71	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.71	gold quality
testis	UBERON:0000473	80.63	gold quality
CA1 field of hippocampus	UBERON:0003881	80.62	silver quality
spinal cord	UBERON:0002240	80.38	gold quality
myometrium	UBERON:0001296	80.25	gold quality
calcaneal tendon	UBERON:0003701	80.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.07	gold quality
blood vessel layer	UBERON:0004797	79.99	gold quality
stomach	UBERON:0000945	79.86	gold quality
cauda epididymis	UBERON:0004360	79.60	gold quality
endocervix	UBERON:0000458	79.44	gold quality
ganglionic eminence	UBERON:0004023	79.35	gold quality
adipose tissue	UBERON:0001013	79.10	gold quality
connective tissue	UBERON:0002384	78.93	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.78	gold quality
ectocervix	UBERON:0012249	78.09	gold quality
esophagus	UBERON:0001043	77.86	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	77.84	gold quality
muscle organ	UBERON:0001630	77.81	gold quality
female reproductive system	UBERON:0000474	77.66	gold quality
uterus	UBERON:0000995	77.66	gold quality
skin of leg	UBERON:0001511	77.29	gold quality
fundus of stomach	UBERON:0001160	77.24	gold quality
right lung	UBERON:0002167	77.14	gold quality
tendon	UBERON:0000043	76.70	gold quality
skin of abdomen	UBERON:0001416	76.49	gold quality
prostate gland	UBERON:0002367	76.27	gold quality
endometrium	UBERON:0001295	76.09	gold quality
zone of skin	UBERON:0000014	75.95	gold quality
upper lobe of left lung	UBERON:0008952	75.86	gold quality
upper lobe of lung	UBERON:0008948	75.76	gold quality
epithelium of mammary gland	UBERON:0003244	75.67	silver quality
layer of synovial tissue	UBERON:0007616	75.57	gold quality
hair follicle	UBERON:0002073	75.53	gold quality
mammary duct	UBERON:0001765	75.44	silver quality
adult mammalian kidney	UBERON:0000082	75.34	gold quality
tibialis anterior	UBERON:0001385	75.34	silver quality
substantia nigra	UBERON:0002038	75.30	gold quality
islet of Langerhans	UBERON:0000006	75.21	gold quality
thoracic mammary gland	UBERON:0005200	75.11	gold quality
mammary gland	UBERON:0001911	75.02	gold quality
germinal epithelium of ovary	UBERON:0001304	74.83	gold quality
tongue squamous epithelium	UBERON:0006919	74.77	gold quality
lower lobe of lung	UBERON:0008949	74.68	gold quality
minor salivary gland	UBERON:0001830	74.50	gold quality
esophagus mucosa	UBERON:0002469	74.47	gold quality
vagina	UBERON:0000996	74.40	gold quality
right lobe of thyroid gland	UBERON:0001119	74.29	gold quality
amygdala	UBERON:0001876	74.20	gold quality
placenta	UBERON:0001987	74.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Locus coeruleus	tissue	20.4
Nucleus accumbens	tissue	18.3
Hippocampus	tissue	17.5	not detected
Adipose tissue	tissue	17.2	not detected
Ovary	tissue	16.7	not detected
Smooth muscle	tissue	15.9	not detected
Testis	tissue	14.9	medium
Seminal vesicle	tissue	14.0	medium
Choroid plexus	tissue	12.3
Postcentral gyrus	tissue	10.2
Fallopian tube	tissue	9.9	low
Spinal cord	tissue	9.8
Endometrium 1	tissue	8.6	not detected
Substantia nigra	tissue	8.5
Tongue	tissue	8.3
Heart muscle	tissue	8.1	not detected
Vagina	tissue	7.8	not detected
Adrenal gland	tissue	7.6	medium
Placenta	tissue	7.5	high
Prostate	tissue	7.5	not detected
Midbrain	tissue	7.3
Cervix	tissue	7.0	not detected
Breast	tissue	6.9	medium
Kidney	tissue	6.1	low
Esophagus	tissue	6.0	not detected
Medulla oblongata	tissue	5.8
Superior colliculi	tissue	5.8
Hippocampal formation	tissue	5.4
Stomach 1	tissue	5.3	low
Thalamus	tissue	5.3
Skin 1	tissue	5.2	low
Thyroid gland	tissue	5.2	low
Appendix	tissue	5.2	low
Periaqueductal gray	tissue	4.9
Salivary gland	tissue	4.8	low
Pituitary gland	tissue	4.5
Gallbladder	tissue	4.4	medium
Urinary bladder	tissue	4.3	low
Pancreas	tissue	4.3	low
Amygdala	tissue	4.3
Corpus callosum	tissue	4.3
Pons	tissue	4.1
Thymus	tissue	4.0
Cerebral cortex	tissue	3.8	not detected
Hypothalamus	tissue	3.8
Entorhinal cortex	tissue	3.8
Temporal cortex	tissue	3.8
Skeletal muscle	tissue	3.7	not detected
Olfactory bulb	tissue	3.6
Epididymis	tissue	3.5	not detected
Motor cortex	tissue	3.3
Septum	tissue	3.3
Insular cortex	tissue	3.3
Basal ganglia	tissue	3.2	low
Prefrontal cortex	tissue	3.1
Lung	tissue	3.1	low
Ventral forebrain	tissue	3.1
Somatosensory cortex	tissue	2.9
Retrosplenial and cingulate cortex	tissue	2.8
Retrosplenial cortex	tissue	2.8

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Area postrema (58.6), Parieto-temporal junction (white matter) (49.7), Nucleus raphe obscurus (47.6), Cerebellar white matter (45.2), Temporal white matter (43.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB3L1, KDM5B

miRNA regulators (miRDB)

Targeting CHST3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 223 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930

Functional genomics

gnomAD constraint: pLI 4.15e-06, LOEUF 1.12, missense Z -0.982 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000373115 — one region, missense o/e 1.03.

Literature-anchored findings (GeneRIF, showing 17)

• report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations (PMID:18513679)
• Sulfation of the galactose residues in the glycosaminoglycan-protein linkage region by recombinant human chondroitin 6-O-sulfotransferase-1. (PMID:18697746)
• homozygous missense mutation (T141M) in exon 3 in all three family members with spondyloepiphyseal dysplasia with cardiac involvement (PMID:19320654)
• Vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance are characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations. (PMID:20830804)
• The results of this study indicated that the critical period for cortical plasticity is regulated by the 4S/6S ratio of CSPGs, which determines the maturation of parvalbumin-expressing interneurons. (PMID:22246436)
• expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of subjects carrying the A allele of rs4148941 (PMID:24216480)
• Sequencing of CHST3 detected a previously unreported homozygous duplication c.407_426dup (p.Thr143Cysfs*80). The mutation is predicted to lead to frameshift and introduction of a premature stopcodon. (PMID:24300290)
• A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss has been described in a consanguineous Pakistani pedigree. (PMID:26572954)
• We describe three consanguineous Indian families with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). It is an autosomal recessive disorder due to mutation in CHST3 gene. (PMID:27753269)
• We show that the CHST3 and CHST13 alleles are significantly more frequent in pulmonary arterial hypertension patients with elevated aminotransferases during therapy with bosentan than those in patients without liver injury. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug-induced liver dysfunction. (PMID:30118797)
• Abnormal expression of chondroitin sulfate sulfotransferases in the articular cartilage of pediatric patients with Kashin-Beck disease. (PMID:31845005)
• Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3. (PMID:32920014)
• Chondroitin 6-sulfate represses keratinocyte proliferation in mouse skin, which is associated with psoriasis. (PMID:33495490)
• Biallelic variants in CHST3 cause Spondyloepiphyseal dysplasia with joint dislocations in three Pakistani kindreds. (PMID:36042462)
• CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum. (PMID:37183573)
• Dampening HOTAIR sensitizes the gastric cancer cells to oxaliplatin through miR-195-5p and ABCG2 pathway. (PMID:37621132)
• Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations. (PMID:37876363)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	chst3a	ENSDARG00000061070
danio_rerio	chst3b	ENSDARG00000116042
mus_musculus	Chst3	ENSMUSG00000057337
rattus_norvegicus	Chst3	ENSRNOG00000000572
drosophila_melanogaster	CG9550	FBGN0031826
drosophila_melanogaster	CG31637	FBGN0051637

Paralogs (6): CHST5 (ENSG00000135702), CHST4 (ENSG00000140835), CHST7 (ENSG00000147119), CHST2 (ENSG00000175040), CHST1 (ENSG00000175264), CHST6 (ENSG00000183196)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1858224) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased prepulse inhibition	2
decreased neutrophil cell number	1
abnormal ovarian folliculogenesis	1
decreased locomotor activity	1
abnormal bone marrow morphology	1
increased coping response	1
decreased aggression towards mice	1
decreased T cell number	1
increased T cell proliferation	1
lymph node hypoplasia	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q92179	75.6%	Diamond
Tetronarce californica	O93403	59.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR7152	ncRNA	102465689
LINC03139	ncRNA	124902447
PSAP	protein-coding	5660
CDH23	protein-coding	64072
ASCC1	protein-coding	51008
SPOCK2	protein-coding	9806

Protein

Protein identifiers

Carbohydrate sulfotransferase 3 — Q7LGC8 (reviewed: Q7LGC8)

Alternative names: Chondroitin 6-O-sulfotransferase 1, Chondroitin 6-sulfotransferase, Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 0

All UniProt accessions (1): Q7LGC8

UniProt curated annotations — full annotation on UniProt →

Function. Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Catalyzes with a lower efficiency the sulfation of Gal residues of keratan sulfate, another glycosaminoglycan. Can also catalyze the sulfation of the Gal residues in sialyl N-acetyllactosamine (sialyl LacNAc) oligosaccharides. May play a role in the maintenance of naive T-lymphocytes in the spleen.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Widely expressed in adult tissues. Expressed in heart, placenta, skeletal muscle and pancreas. Also expressed in various immune tissues such as spleen, lymph node, thymus and appendix.

Post-translational modifications. N-glycosylated.

Disease relevance. Spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD) [MIM:143095] A bone dysplasia clinically characterized by dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disk degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sulfotransferase 1 family. Gal/GlcNAc/GalNAc subfamily.

RefSeq proteins (3): NP_001428130, NP_001428131, NP_004264* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000863	Sulfotransferase_dom	Domain
IPR016469	Carbohydrate_sulfotransferase	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR051135	Gal/GlcNAc/GalNAc_ST	Family

Pfam: PF00685

Enzyme classification (BRENDA)

• EC 2.8.2.17 — chondroitin 6-sulfotransferase (BRENDA: 7 organisms, 62 substrates, 14 inhibitors, 31 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’-PHOSPHOADENYLYL SULFATE	0.0003–0.0042	6
CHONDROITIN	0.0008–0.15	6
3’-PHOSPHOADENYLYLSULFATE	0.0001–0.0333	5
CHONDROITIN 4-SULFATE	0.0005–0.038	2
KERATAN SULFATE	0.0029–0.005	2
DECASACCHARIDE	0.9	1
DESULFATED CHONDROITIN SULFATE	1.8	1
DODECASACCHARIDE	0.48	1
GLCUABETA(1->3)GALNAC(4S)BETA(1->4)GLCUABETA(1->	0.05	1
HEXASACCHARIDE	5	1
N-ACETYLGALACTOSAMINE 4-SULFATE	0.36	1
NATIVE CHONDROITIN	0.06	1
OCTASACCHARIDE	2.5	1
UDP-N-ACETYLGALACTOSAMINE 4-SULFATE	0.027	1

Catalyzed reactions (Rhea)

• chondroitin beta-D-glucuronate + n 3’-phosphoadenylyl sulfate = chondroitin 6’-sulfate + n adenosine 3’,5’-bisphosphate + n H(+) (RHEA:11108)

UniProt features (22 total): sequence variant 7, glycosylation site 6, topological domain 2, sequence conflict 2, binding site 2, chain 1, transmembrane region 1, region of interest 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7LGC8-F1	80.58	0.57

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted membrane proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of the musculoskeletal system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; golgi apparatus

Antibody reliability (HPA): IH enhanced · IF approved

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 (2)

Position	Role
141–147	3’-phosphoadenylyl sulfate
301–309	3’-phosphoadenylyl sulfate

Glycosylation sites (6)

Type	Positions
N-linked (glcnac…) asparagine	256, 420, 464, 63, 74, 96

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 12; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-3595172	Defective CHST3 causes SEDCJD ⚕	curated
R-HSA-2022870	CS-GAG biosynthesis	curated
R-HSA-2022854	Keratan sulfate biosynthesis	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-3560782	Diseases associated with glycosaminoglycan metabolism ⚕	—
R-HSA-3781865	Diseases of glycosylation ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-1793185	Chondroitin sulfate/dermatan sulfate metabolism	—
R-HSA-1630316	Glycosaminoglycan metabolism	—
R-HSA-1638074	Keratan sulfate/keratin metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives	—

MSigDB gene sets: 489 (showing top): MODULE_52, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, DOANE_BREAST_CANCER_CLASSES_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CHONDROITIN_SULFATE_PROTEOGLYCAN_BIOSYNTHETIC_PROCESS, MODULE_118, BROWNE_HCMV_INFECTION_48HR_DN, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, CAGCAGG_MIR370, ONKEN_UVEAL_MELANOMA_UP, MODULE_379, AMIT_EGF_RESPONSE_120_HELA, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): carbohydrate metabolic process (GO:0005975), N-acetylglucosamine metabolic process (GO:0006044), sulfur compound metabolic process (GO:0006790), keratan sulfate proteoglycan biosynthetic process (GO:0018146), chondroitin sulfate proteoglycan biosynthetic process (GO:0050650), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (6): N-acetylglucosamine 6-O-sulfotransferase activity (GO:0001517), chondroitin 6-sulfotransferase activity (GO:0008459), keratan sulfotransferase activity (GO:0045130), sulfotransferase activity (GO:0008146), transferase activity (GO:0016740), proteoglycan sulfotransferase activity (GO:0050698)

GO Cellular Component (2): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Glycosaminoglycan metabolism	2
Keratan sulfate/keratin metabolism	1
Chondroitin sulfate/dermatan sulfate metabolism	1
Diseases associated with glycosaminoglycan metabolism	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Diseases of glycosylation	1
Diseases of metabolism	1
Disease	1
Metabolism	1

GO top-level categories

17 GO namespaces:

Category	Terms
metabolic process	2
proteoglycan biosynthetic process	2
sulfotransferase activity	2
primary metabolic process	1
amino sugar metabolic process	1
keratan sulfate proteoglycan metabolic process	1
chondroitin sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
chondroitin sulfotransferase activity	1
proteoglycan 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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
chondroitin sulfate proteoglycan biosynthetic process	BP	direct assay
sulfur compound metabolic process	BP	direct assay
chondroitin 6-sulfotransferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 514 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHST3	SULT1C4	O75897	779
CHST3	SULT1C3	Q6IMI6	772
CHST3	SULT1B1	O43704	769
CHST3	CHST11	Q9NPF2	762
CHST3	LUM	P51884	749
CHST3	CHST12	Q9NRB3	736
CHST3	CHST13	Q8NET6	735
CHST3	KERA	O60938	716
CHST3	CHST15	Q7LFX5	704
CHST3	CHST14	Q8NCH0	647
CHST3	CHSY1	Q86X52	646
CHST3	NTAN1	Q96AB6	617
CHST3	HS2ST1	Q7LGA3	570
CHST3	CSGALNACT2	Q8N6G5	567
CHST3	CHPF	Q8IZ52	563

IntAct

Human interaction partners of CHST3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
OFD1	physical association	0.000	1

BioGRID (22 interactions; top human partners by supporting records): AVP (Affinity Capture-MS; 2 records), CRP (Affinity Capture-MS; 2 records), PTCH1 (Affinity Capture-MS; 2 records), SCGB2A2 (Affinity Capture-MS; 2 records), AGO2 (Affinity Capture-RNA), C1orf54 (Affinity Capture-MS), C1QTNF7 (Affinity Capture-MS), CLEC12B (Affinity Capture-MS), ELAVL1 (Affinity Capture-RNA), KIAA1429 (Affinity Capture-RNA), MSMB (Affinity Capture-MS), OFD1 (Affinity Capture-MS), PARP12 (Proximity Label-MS), PDGFRA (Affinity Capture-MS), SLC39A11 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for CHST3: 476 ClinVar records (53 pathogenic / likely pathogenic); 7 PharmGKB clinical annotations; 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	23
Uncertain significance	221
Likely benign	145
Benign	32

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 53 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
871056	NM_004273.5(CHST3):c.168_186dup (p.Asn63fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
955770	NM_004273.5(CHST3):c.1291dup (p.Ser431fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
522996	NM_004273.5(CHST3):c.1312C>T (p.Gln438Ter)	Pathogenic	criteria provided, single submitter	2
478822	NM_004273.5(CHST3):c.904G>C (p.Asp302His)	Pathogenic	criteria provided, single submitter	1
478823	NM_004273.5(CHST3):c.491C>T (p.Pro164Leu)	Pathogenic	criteria provided, single submitter	1
632140	NM_004273.5(CHST3):c.512_513del (p.Thr171fs)	Pathogenic	criteria provided, single submitter	1
694680	NM_004273.5(CHST3):c.1254GAA[1] (p.Lys419del)	Pathogenic	criteria provided, single submitter	1
1039079	NM_004273.5(CHST3):c.334G>T (p.Glu112Ter)	Pathogenic	criteria provided, single submitter	1
1406206	NM_004273.5(CHST3):c.362dup (p.Glu122fs)	Pathogenic	criteria provided, single submitter	1
1445618	NM_004273.5(CHST3):c.271C>T (p.Gln91Ter)	Pathogenic	criteria provided, single submitter	1
1452559	NM_004273.5(CHST3):c.1150_1166del (p.Glu384fs)	Pathogenic	criteria provided, single submitter	1
1454776	NM_004273.5(CHST3):c.763del (p.Leu255fs)	Pathogenic	criteria provided, single submitter	1
1458337	NM_004273.5(CHST3):c.238del (p.Ser79_Leu80insTer)	Pathogenic	criteria provided, single submitter	1
1474566	NM_004273.5(CHST3):c.1177del (p.Pro392_Leu393insTer)	Pathogenic	criteria provided, single submitter	1
1685635	NM_004273.5(CHST3):c.141-1G>C	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CHST3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 268):

Position(s)	Effect	Δscore	Sites
10:72007170–72007171	acceptor_loss	1.0000	4
10:72005734–72005735	acceptor_loss	0.9900	6
10:72005900	donor_gain	0.9900
10:72005964	donor_gain	0.9900
10:72007169	acceptor_gain	0.9900
10:72007170–72007171	acceptor_loss	0.9900	2
10:72005793	donor_gain	0.9800
10:72005983–72005984	donor_loss	0.9800	5
10:72008446	donor_gain	0.9800
10:71964611	donor_gain	0.9700

AlphaMissense

1,020 missense substitutions predicted likely pathogenic (of 3,117 scored), across 257 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D302	8	0.995	0.999
F220	8	0.973	0.999
F159	8	0.969	0.994
F147	8	0.965	0.997
F152	8	0.958	0.997
F314	8	0.956	0.997
S225	8	0.941	0.999
D289	8	0.929	0.989
F451	8	0.906	0.964
H167	8	0.904	0.990
D373	8	0.904	0.970
H214	8	0.848	0.956
C234	7	0.998	0.999
F162	7	0.997	0.999
E163	7	0.997	1.000
C229	7	0.997	0.999
C252	7	0.996	0.999
C264	7	0.996	0.998
W428	7	0.995	1.000
C198	7	0.994	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:603799 | disease phenotypes: MIM:143095, MIM:245600, MIM:150250

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
spondyloepiphyseal dysplasia with congenital joint dislocations	Definitive	Autosomal recessive	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
spondyloepiphyseal dysplasia with congenital joint dislocations	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 11 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Congenital disorders of glycosylation	green
DDG2P	green
Fetal anomalies	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Skeletal dysplasia	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (3): spondyloepiphyseal dysplasia with congenital joint dislocations (MONDO:0007738), Larsen-like syndrome, B3GAT3 type (MONDO:0009511), Larsen syndrome (MONDO:0007875)

Orphanet (3): CHST3-related skeletal dysplasia (Orphanet:263463), Larsen-like syndrome, B3GAT3 type (Orphanet:284139), Larsen syndrome (Orphanet:503)

HPO phenotypes

showing 60 of 148 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000274	Small face
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000520	Proptosis
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000574	Thick eyebrow
HP:0000592	Blue sclerae
HP:0000646	Amblyopia
HP:0000684	Delayed eruption of teeth
HP:0000687	Widely spaced teeth
HP:0000691	Microdontia
HP:0000768	Pectus carinatum
HP:0000774	Narrow chest
HP:0000776	Congenital diaphragmatic hernia
HP:0000878	11 pairs of ribs
HP:0000914	Shield chest
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000973	Cutis laxa
HP:0000974	Hyperextensible skin
HP:0001087	Developmental glaucoma
HP:0001090	Abnormally large globe
HP:0001156	Brachydactyly
HP:0001222	Spatulate thumbs
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001363	Craniosynostosis
HP:0001371	Flexion contracture
HP:0001373	Joint dislocation
HP:0001382	Joint hypermobility
HP:0001552	Barrel-shaped chest
HP:0001623	Breech presentation
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001634	Mitral valve prolapse
HP:0001640	Cardiomegaly
HP:0001642	Pulmonic stenosis
HP:0001647	Bicuspid aortic valve
HP:0001650	Aortic valve stenosis
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale

GWAS associations

5 associations:

Study	Trait	p-value
GCST002225_1	Disc degeneration (lumbar)	4e-8
GCST002225_2	Disc degeneration (lumbar)	1e-6
GCST012255_1	Response to antioxidants and zinc in age-related macular degeneration (disease progression)	3e-6
GCST007102_18	Seasonality and depression	6e-6
GCST004862_85	Itch intensity from mosquito bite adjusted by bite size	8e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0006876	seasonality measurement
EFO:0008336	disease progression measurement

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
C537283	Gollop Coates syndrome *(supp.)*
C580241	Larsen Syndrome *(supp.)*
C537874	Larsen syndrome, recessive type *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

7 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs12418	Efficacy	3	docetaxel;thalidomide	Prostatic Neoplasms
rs1871450	Efficacy,Toxicity	3	docetaxel;thalidomide	Prostatic Neoplasms
rs4148943	Efficacy	3	docetaxel;thalidomide	Prostatic Neoplasms
rs4148945	Efficacy,Toxicity	3	docetaxel;thalidomide	Prostatic Neoplasms
rs4148947	Efficacy	3	docetaxel;thalidomide	Prostatic Neoplasms
rs4148950	Efficacy,Toxicity	3	docetaxel;thalidomide	Prostatic Neoplasms
rs730720	Efficacy	3	docetaxel;thalidomide	Prostatic Neoplasms

PharmGKB variants

7 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12418	CHST3	3	2.00	1	docetaxel;thalidomide
rs730720	CHST3	3	2.00	1	docetaxel;thalidomide
rs1871450	CHST3	3	3.50	1	docetaxel;thalidomide
rs4148943	CHST3	3	2.00	1	docetaxel;thalidomide
rs4148945	CHST3	3	3.00	1	docetaxel;thalidomide
rs4148947	CHST3	3	2.00	1	docetaxel;thalidomide
rs4148950	CHST3	3	3.50	1	docetaxel;thalidomide

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

10 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs12418	docetaxel, thalidomide	Efficacy	Allele A is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele G.	PMID:20038957
rs1871450	docetaxel, thalidomide	Toxicity	Allele A is associated with increased risk of toxicity when treated with docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele G.	PMID:20038957
rs1871450	docetaxel, thalidomide	Efficacy	Allele A is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele G.	PMID:20038957
rs4148943	docetaxel, thalidomide	Efficacy	Allele C is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele T.	PMID:20038957
rs4148945	docetaxel, thalidomide	Efficacy	Allele C is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele T.	PMID:20038957
rs4148945	docetaxel, thalidomide	Toxicity	Allele C is associated with increased risk of toxicity when treated with docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele T.	PMID:20038957
rs730720	docetaxel, thalidomide	Efficacy	Allele C is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele T.	PMID:20038957
rs4148950	docetaxel, thalidomide	Toxicity	Allele A is associated with increased risk of toxicity when treated with docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele G.	PMID:20038957
rs4148950	docetaxel, thalidomide	Efficacy	Allele A is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele G.	PMID:20038957
rs4148947	docetaxel, thalidomide	Efficacy	Allele T is associated with increased response to docetaxel and thalidomide in people with Prostatic Neoplasms as compared to allele C.	PMID:20038957

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
2-palmitoylglycerol	increases expression	1
clothianidin	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
apple polyphenol extract	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Biological Factors	decreases expression	1
Calcitriol	increases expression	1
Chromium	increases expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

1 trials:

NCT	Phase	Status	Title
NCT05052554	Phase 1	WITHDRAWN	Study With QR-504a to Evaluate Safety, Tolerability & Corneal Endothelium Molecular Biomarker(s) in Subjects With FECD3