EXTL1

Summary

EXTL1 (exostosin like glycosyltransferase 1, HGNC:3515) is a protein-coding gene on chromosome 1p36.11, encoding Exostosin-like 1 (Q92935). Glycosyltransferase required for the biosynthesis of heparan-sulfate (HS).

This gene is a member of the multiple exostoses (EXT) family of glycosyltransferases, which function in the chain polymerization of heparan sulfate and heparin. The encoded protein harbors alpha 1,4- N-acetylglucosaminyltransferase activity, and is involved in chain elongation of heparan sulfate and possibly heparin.

Source: NCBI Gene 2134 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 124 total
• MANE Select transcript: NM_004455

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3515
Approved symbol	EXTL1
Name	exostosin like glycosyltransferase 1
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	EXTL, MGC70794
Ensembl gene	ENSG00000158008
Ensembl biotype	protein_coding
OMIM	601738
Entrez	2134

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000374280, ENST00000470037, ENST00000481377, ENST00000484339, ENST00000882616, ENST00000882617, ENST00000882618, ENST00000882619, ENST00000882620, ENST00000882621

RefSeq mRNA: 1 — MANE Select: NM_004455 NM_004455

CCDS: CCDS271

Canonical transcript exons

ENST00000374280 — 11 exons

Exon	Start	End
ENSE00001036492	26033229	26033315
ENSE00001036493	26032396	26032485
ENSE00001036509	26031460	26031566
ENSE00001462999	26035165	26036464
ENSE00001463001	26021775	26023425
ENSE00003461017	26029600	26029707
ENSE00003480117	26033696	26033856
ENSE00003484308	26034836	26035004
ENSE00003633551	26030476	26030595
ENSE00003641360	26029193	26029286
ENSE00003683033	26031132	26031264

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 91.00.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9708 / max 100.4753, expressed in 301 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1551	0.9378	300
1552	0.0329	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	91.00	gold quality
tibial nerve	UBERON:0001323	88.92	gold quality
prefrontal cortex	UBERON:0000451	88.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.34	gold quality
cingulate cortex	UBERON:0003027	87.26	gold quality
anterior cingulate cortex	UBERON:0009835	87.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.17	gold quality
frontal cortex	UBERON:0001870	84.96	gold quality
amygdala	UBERON:0001876	84.91	gold quality
neocortex	UBERON:0001950	84.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.63	gold quality
tibia	UBERON:0000979	84.02	gold quality
sural nerve	UBERON:0015488	83.93	gold quality
primary visual cortex	UBERON:0002436	83.28	gold quality
cerebral cortex	UBERON:0000956	82.76	gold quality
Brodmann (1909) area 10	UBERON:0013541	80.61	gold quality
telencephalon	UBERON:0001893	80.02	gold quality
Ammon’s horn	UBERON:0001954	79.79	gold quality
temporal lobe	UBERON:0001871	79.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.88	gold quality
apex of heart	UBERON:0002098	78.76	gold quality
occipital lobe	UBERON:0002021	78.74	gold quality
forebrain	UBERON:0001890	77.57	gold quality
middle temporal gyrus	UBERON:0002771	77.41	silver quality
Brodmann (1909) area 46	UBERON:0006483	76.78	silver quality
nucleus accumbens	UBERON:0001882	75.55	gold quality
gastrocnemius	UBERON:0001388	75.45	gold quality
brain	UBERON:0000955	75.44	gold quality
central nervous system	UBERON:0001017	75.32	gold quality
muscle of leg	UBERON:0001383	75.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting EXTL1, 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-4283	100.00	66.42	2097
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-6821-3P	95.21	66.79	578
HSA-MIR-663A	94.99	63.54	378
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352
HSA-MIR-6790-3P	88.15	62.55	113

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ext1c	ENSDARG00000035649
mus_musculus	Extl1	ENSMUSG00000028838
rattus_norvegicus	Extl1	ENSRNOG00000016776
drosophila_melanogaster	ttv	FBGN0265974
caenorhabditis_elegans		WBGENE00004360

Paralogs (4): EXTL3 (ENSG00000012232), EXT2 (ENSG00000151348), EXTL2 (ENSG00000162694), EXT1 (ENSG00000182197)

Protein

Protein identifiers

Exostosin-like 1 — Q92935 (reviewed: Q92935)

Alternative names: Exostosin-L, Glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, Multiple exostosis-like protein

All UniProt accessions (1): Q92935

UniProt curated annotations — full annotation on UniProt →

Function. Glycosyltransferase required for the biosynthesis of heparan-sulfate (HS). Transfers N-acetyl-alpha-D-glucosamine to the nascent HS chain (GlcNAcT-II activity). Appears to lack GlcNAcT I and GlcAT-II activities.

Subcellular location. Endoplasmic reticulum membrane.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the glycosyltransferase 47 family.

RefSeq proteins (1): NP_004446* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004263	Exostosin	Family
IPR015338	GT64_dom	Domain
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily
IPR040911	Exostosin_GT47	Domain

Pfam: PF03016, PF09258

Catalyzed reactions (Rhea), 1 shown:

• 3-O-{(1->4)-beta-D-GlcA-(1->4)-alpha-D-GlcNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl}-L-seryl-[protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-{alpha-D-GlcNAc-(1->4)-beta-D-GlcA-(1->4)-alpha-D-GlcNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl}-L-seryl-[protein] + UDP + H(+) (RHEA:16213)

UniProt features (11 total): topological domain 2, sequence variant 2, region of interest 2, chain 1, transmembrane region 1, compositionally biased region 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92935-F1	80.09	0.48

Functional residue map

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

Disulfide bonds (1): 584–634

Glycosylation sites (1): 269

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes

MSigDB gene sets: 106 (showing top): REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MEF2_02, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MARTIN_VIRAL_GPCR_SIGNALING_DN, ARGGGTTAA_UNKNOWN, CHO_NR4A1_TARGETS, MODULE_400, GOBP_PROTEIN_O_LINKED_GLYCOSYLATION, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS

GO Biological Process (3): skeletal system development (GO:0001501), heparan sulfate proteoglycan biosynthetic process (GO:0015012), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (6): acetylglucosaminyltransferase activity (GO:0008375), glucuronosyltransferase activity (GO:0015020), glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity (GO:0050508), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
IRE1alpha activates chaperones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
UDP-glycosyltransferase activity	2
hexosyltransferase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
system development	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
acetylglucosaminyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXTL1	TRAP1	Q12931	714
EXTL1	NDST3	O95803	642
EXTL1	GLCE	O94923	639
EXTL1	NDST2	P52849	609
EXTL1	HS2ST1	Q7LGA3	591
EXTL1	NDST1	P52848	589
EXTL1	CHSY1	Q86X52	561
EXTL1	HS6ST1	O60243	556
EXTL1	CSGALNACT1	Q8TDX6	554
EXTL1	B4GALT7	Q9UBV7	543
EXTL1	XYLT1	Q86Y38	543
EXTL1	NDST4	Q9H3R1	540
EXTL1	HS3ST1	O14792	528
EXTL1	B3GAT3	O94766	527
EXTL1	CHPF2	Q9P2E5	519

IntAct

18 interactions, top by confidence:

A	B	Type	Score
FNDC9	EXTL1	psi-mi:“MI:0915”(physical association)	0.560
EXTL1	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
EXTL1	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
EXTL1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
CLDN9	EXTL1	psi-mi:“MI:0915”(physical association)	0.560
EXTL1	GRB2	psi-mi:“MI:0915”(physical association)	0.400
EXTL1	SDR16C5	psi-mi:“MI:0915”(physical association)	0.370
EXTL1	FNDC9	psi-mi:“MI:0915”(physical association)	0.000
EXTL1	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
EXTL1	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000
EXTL1	CLDN9	psi-mi:“MI:0915”(physical association)	0.000
EXTL1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): EXTL1 (Two-hybrid), EXTL1 (Two-hybrid), EXTL1 (Two-hybrid), FNDC9 (Two-hybrid), CLDN9 (Two-hybrid), EXTL1 (Protein-peptide), SDR16C5 (Two-hybrid)

ESM2 similar proteins: A7MBM2, D3KCC4, E9PY61, L5KLU7, O95382, P04087, P32958, Q03395, Q08E36, Q0V8J4, Q14296, Q1KZG0, Q49LS1, Q5GH72, Q642B3, Q643R3, Q66K66, Q674R7, Q6EBV9, Q6F5E8, Q6MG64, Q6NUI2, Q6P5W5, Q6PRD1, Q6ZMH5, Q7TNJ2, Q7Z7M1, Q7Z7M8, Q86WK7, Q8BG75, Q8BP97, Q8CG70, Q8CIP5, Q8IUH8, Q8IVL6, Q8IZF5, Q8IZY2, Q8K1S7, Q8N2G8, Q8NCW0

Diamond homologs: A5D7I4, A9X1C8, O01704, O77783, P70428, P97464, Q16394, Q33AH8, Q5IGR6, Q5IGR7, Q5IGR8, Q5RBC3, Q84WB7, Q92935, Q93063, Q9C975, Q9ES89, Q9JK82, Q9JKV7, Q9LY62, Q9SSE8, Q9UBQ6, Q9V730, Q9XZ08, Q9Y169, A2Y6Z7, A9RGD8, O01705, O43909, Q3E9A4, Q53WK1, Q6H4N0, Q6NMM8, Q7XLG3, Q8S1X7, Q8S1X8, Q8S1X9, Q940Q8, Q94AA9, Q9FFN2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EXTL1	down-regulates	SHH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2263 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26030468:T:A	acceptor_gain	1.0000
1:26030471:TCCA:T	acceptor_loss	1.0000
1:26030472:CCA:C	acceptor_loss	1.0000
1:26030473:CAG:C	acceptor_loss	1.0000
1:26030593:G:GT	donor_gain	1.0000
1:26030594:AGGT:A	donor_loss	1.0000
1:26030595:GG:G	donor_loss	1.0000
1:26030596:GTG:G	donor_loss	1.0000
1:26030597:T:A	donor_loss	1.0000
1:26031263:GG:G	donor_gain	1.0000
1:26031264:GG:G	donor_gain	1.0000
1:26033311:G:GG	donor_gain	1.0000
1:26034832:CCA:C	acceptor_loss	1.0000
1:26034835:GGT:G	acceptor_gain	1.0000
1:26034977:C:T	donor_gain	1.0000
1:26034990:G:GT	donor_gain	1.0000
1:26035161:TTAG:T	acceptor_loss	1.0000
1:26035163:A:AG	acceptor_gain	1.0000
1:26035163:AGG:A	acceptor_loss	1.0000
1:26035164:G:GG	acceptor_gain	1.0000
1:26035164:GGC:G	acceptor_gain	1.0000
1:26035164:GGCGC:G	acceptor_gain	1.0000
1:26023426:G:GG	donor_gain	0.9900
1:26029180:T:G	acceptor_gain	0.9900
1:26029282:TGCAG:T	donor_loss	0.9900
1:26029284:CAGG:C	donor_loss	0.9900
1:26029285:AGG:A	donor_loss	0.9900
1:26029286:GG:G	donor_loss	0.9900
1:26029287:G:T	donor_loss	0.9900
1:26029288:T:G	donor_loss	0.9900

AlphaMissense

4355 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26029663:T:A	W313R	0.988
1:26029663:T:C	W313R	0.988
1:26029665:G:C	W313C	0.986
1:26029665:G:T	W313C	0.986
1:26033736:G:C	R520P	0.984
1:26035315:C:A	R667S	0.979
1:26034926:T:A	N590K	0.978
1:26034926:T:G	N590K	0.978
1:26033280:A:C	S495R	0.973
1:26033282:C:A	S495R	0.973
1:26033282:C:G	S495R	0.973
1:26033717:T:A	W514R	0.973
1:26033717:T:C	W514R	0.973
1:26031182:G:C	W384C	0.970
1:26031182:G:T	W384C	0.970
1:26031480:T:C	F419L	0.970
1:26031482:C:A	F419L	0.970
1:26031482:C:G	F419L	0.970
1:26023226:T:C	F194L	0.969
1:26023228:T:A	F194L	0.969
1:26023228:T:G	F194L	0.969
1:26031483:A:C	S420R	0.967
1:26031485:C:A	S420R	0.967
1:26031485:C:G	S420R	0.967
1:26023188:C:A	A181D	0.964
1:26031481:T:C	F419S	0.964
1:26029227:T:C	F272L	0.963
1:26029229:C:A	F272L	0.963
1:26029229:C:G	F272L	0.963
1:26035320:G:C	K668N	0.959

dbSNP variants (sampled 300 via entrez): RS1000023137 (1:26028898 G>C), RS1000078756 (1:26022186 C>A,T), RS1001154204 (1:26025885 G>T), RS1001422598 (1:26035999 C>A,T), RS1001523480 (1:26026183 G>A,T), RS1001592617 (1:26033920 C>T), RS1001665364 (1:26026966 C>T), RS1001708909 (1:26030331 T>C), RS1001750709 (1:26020928 G>A), RS1001874254 (1:26032115 G>C), RS1001928068 (1:26032533 T>G), RS1001957367 (1:26036223 T>C), RS1002029833 (1:26025797 G>A), RS1002096404 (1:26027323 A>C,G), RS1002399112 (1:26025400 A>T)

Disease associations

OMIM: gene MIM:601738 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	increases expression	2
perfluorotetradecanoic acid	increases expression	1
testosterone enanthate	affects expression	1
bisphenol A	decreases methylation	1
perfluorobutyric acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
Temozolomide	affects response to substance	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Ethanol	increases expression	1
Arsenic	affects methylation	1
Carmustine	affects response to substance	1
Doxorubicin	decreases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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