EXTL3

Summary

EXTL3 (exostosin like glycosyltransferase 3, HGNC:3518) is a protein-coding gene on chromosome 8p21.1, encoding Exostosin-like 3 (O43909). Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS).

This gene encodes a single-pass membrane protein which functions as a glycosyltransferase. The encoded protein catalyzes the transfer of N-acetylglucosamine to glycosaminoglycan chains. This reaction is important in heparin and heparan sulfate synthesis. Alternative splicing results in the multiple transcript variants.

Source: NCBI Gene 2137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunoskeletal dysplasia with neurodevelopmental abnormalities (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 595 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 148
• MANE Select transcript: NM_001440

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3518
Approved symbol	EXTL3
Name	exostosin like glycosyltransferase 3
Location	8p21.1
Locus type	gene with protein product
Status	Approved
Aliases	botv, REGR
Ensembl gene	ENSG00000012232
Ensembl biotype	protein_coding
OMIM	605744
Entrez	2137

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 19 protein_coding, 13 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000220562, ENST00000454906, ENST00000517738, ENST00000518223, ENST00000519288, ENST00000519886, ENST00000520679, ENST00000520940, ENST00000521473, ENST00000521532, ENST00000522698, ENST00000522725, ENST00000523271, ENST00000696177, ENST00000696178, ENST00000696179, ENST00000696180, ENST00000696181, ENST00000696182, ENST00000696183, ENST00000696184, ENST00000696185, ENST00000696186, ENST00000696187, ENST00000696188, ENST00000869871, ENST00000869872, ENST00000926356, ENST00000926357, ENST00000926358, ENST00000926359, ENST00000926360, ENST00000953976, ENST00000953977, ENST00000953978

RefSeq mRNA: 1 — MANE Select: NM_001440 NM_001440

CCDS: CCDS6070

Canonical transcript exons

ENST00000220562 — 7 exons

Exon	Start	End
ENSE00000686606	28743086	28743214
ENSE00000818721	28715585	28718207
ENSE00001216907	28713457	28713550
ENSE00003494778	28737519	28737663
ENSE00003590485	28731223	28731350
ENSE00003966356	28750657	28755599
ENSE00003966374	28701501	28701659

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 94.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4294 / max 204.9543, expressed in 1814 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88215	7.7742	1721
88212	7.6372	1772
88211	3.5600	941
88213	0.7360	468
88214	0.7220	470

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	94.95	gold quality
ventricular zone	UBERON:0003053	93.88	gold quality
cortical plate	UBERON:0005343	93.51	gold quality
ganglionic eminence	UBERON:0004023	92.74	gold quality
islet of Langerhans	UBERON:0000006	91.61	gold quality
adrenal tissue	UBERON:0018303	89.64	gold quality
prefrontal cortex	UBERON:0000451	88.43	gold quality
mucosa of stomach	UBERON:0001199	87.11	gold quality
frontal pole	UBERON:0002795	87.03	gold quality
apex of heart	UBERON:0002098	86.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.92	gold quality
right atrium auricular region	UBERON:0006631	85.72	gold quality
heart left ventricle	UBERON:0002084	85.59	gold quality
smooth muscle tissue	UBERON:0001135	85.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.27	gold quality
middle frontal gyrus	UBERON:0002702	85.19	silver quality
cardiac ventricle	UBERON:0002082	85.12	gold quality
paraflocculus	UBERON:0005351	84.99	silver quality
left adrenal gland	UBERON:0001234	84.67	gold quality
embryo	UBERON:0000922	84.52	gold quality
frontal cortex	UBERON:0001870	84.49	gold quality
adrenal gland	UBERON:0002369	84.43	gold quality
left adrenal gland cortex	UBERON:0035825	84.37	gold quality
heart	UBERON:0000948	84.35	gold quality
cardiac atrium	UBERON:0002081	84.33	gold quality
pancreatic ductal cell	CL:0002079	84.20	silver quality
muscle of leg	UBERON:0001383	83.98	gold quality
neocortex	UBERON:0001950	83.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.95	gold quality
right coronary artery	UBERON:0001625	83.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.98
E-MTAB-6386	no	77.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting EXTL3, 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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059

Literature-anchored findings (GeneRIF, showing 17)

• These results suggest that EXTL3/EXTR1 is a cell surface Reg receptor that binds to Reg protein. (PMID:10753861)
• We conclude that EXTL3 promoter methylation and its related loss of EXTL3 expression are involved in the loss of HS expression in mucinous CRCs. (PMID:18543267)
• HIP enhanced EXTL3 translocation from the membrane to the nucleus, in support of a model whereby EXTL3 mediates HIP signaling for islet neogenesis. (PMID:19158046)
• A missense mutation involving the exon 3 of the EXTL3 gene in the case of obstructing colon cancer is described in a 31-year-old patient affected by hereditary multiple exostoses. (PMID:19653241)
• Lysosomal glycosaminoglycan levels in mucopolysaccharidosis are reduced by EXTL3 gene silencing. (PMID:19690583)
• Regenerating islet-derived 1alpha (Reg-1alpha) protein is new neuronal secreted factor that stimulates neurite outgrowth via exostosin Tumor-like 3 (EXTL3) receptor. (PMID:22158612)
• Recombinant EXTL2 showed weak ability to transfer N-acetylgalactosamine to heparan sulfate precursor molecules but also, that EXTL2 exhibited much stronger in vitro N-acetylglucosamine-transferase activity related to elongation of heparan sulfate chains. (PMID:25829497)
• We show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities. (PMID:28132690)
• EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development. (PMID:28148688)
• EXTL3 missense mutation is associated with spondylo-epi-metaphyseal dysplasia. (PMID:28331220)
• EXTL3 mutations are associated with spondylo-epi-metaphyseal dysplasia with immunodeficiency. (PMID:28446799)
• Human lumenal N-glycosylated EXTL3 (EXTL3DeltaN) was cloned, expressed in human embryonic kidney cells, and purified. Various biophysical and biochemical approaches were then employed to elucidate the N-glycosylation sites and the function of their attached N-glycans. (PMID:29346724)
• EXTL3-interacting endometriosis-specific serum factors induce colony formation of endometrial stromal cells. (PMID:31467315)
• Spondyloepimetaphyseal dysplasia EXTL3-deficient type: Long-term follow-up and review of the literature. (PMID:34089299)
• REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. (PMID:34099862)
• Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion. (PMID:36181793)
• EXTL3 and NPC1 are mammalian host factors for Autographa californica multiple nucleopolyhedrovirus infection. (PMID:39231976)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	extl3	ENSDARG00000026811
mus_musculus	Extl3	ENSMUSG00000021978
rattus_norvegicus	Extl3	ENSRNOG00000013581
drosophila_melanogaster	botv	FBGN0027535
caenorhabditis_elegans		WBGENE00004361

Paralogs (4): EXT2 (ENSG00000151348), EXTL1 (ENSG00000158008), EXTL2 (ENSG00000162694), EXT1 (ENSG00000182197)

Protein

Protein identifiers

Exostosin-like 3 — O43909 (reviewed: O43909)

Alternative names: EXT-related protein 1, Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, Hereditary multiple exostoses gene isolog, Multiple exostosis-like protein 3, Putative tumor suppressor protein EXTL3

All UniProt accessions (8): O43909, A0A384NPY9, A0A8Q3SIB8, A0A8Q3SIF4, A0A8Q3SII2, A0A8Q3SIK7, H0YB01, H0YBJ7

UniProt curated annotations — full annotation on UniProt →

Function. Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). Initiates HS synthesis by transferring the first N-acetyl-alpha-D-glucosamine (alpha-GlcNAc) residue (GlcNAcT-I activity) to the tetrasaccharide linker (GlcA-Gal-Gal-Xyl-)Ser core linker. May also transfer alpha-GlcNAc residues during HS elongation (GlcNAcT-II activity). Lacks glucuronyl transferase II (GlcAT-II) activity. Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). Through the synthesis of HS, regulates postnatal pancreatic islet maturation and insulin secretion. Receptor for REG3A, REG3B and REG3G, induces the activation of downstream signaling pathways such as PI3K-AKT or RAS-RAF-MEK-ERK signaling pathway. Required for the function of REG3A in regulating keratinocyte proliferation and differentiation. Required for the inhibition of skin inflammation mediated by REG3A through the activation of PI3K-AKT-STAT3 pathway. Required for the function of REG3A and REG3G in glucose tolerance in pancreas. Expressed in microglia, is activated by nociceptor-derived REG3G in response to endotoxins, leading to the inhibition of kynurenine pathway to prevent endotoxic death.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with REG3A.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. Cell membrane. Nucleus.

Tissue specificity. Ubiquitous. Expressed in keratinocytes. Expressed in pancreas.

Disease relevance. Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) [MIM:617425] An autosomal recessive disorder characterized by variable skeletal abnormalities and neurodevelopmental defects. Neurologic manifestations include intellectual disability and motor delay. Some patients manifest hypotonia and seizures. Skeletal features include disproportionate short stature, cervical malformations, epiphyseal and metaphyseal dysplasia, and rarely premature craniosynostosis with progressive microcephaly. Severe combined immunodeficiency with a complete absence of T cells is observed in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal glycosyltransferase domain (GT47) does not bind UDP and is therefore unlikely to possess glycosyltransferase activity.

Pathway. Glycan metabolism; heparan sulfate biosynthesis.

Similarity. Belongs to the glycosyltransferase 47 family.

RefSeq proteins (1): NP_001431* (*=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

Enzyme classification (BRENDA):

• EC 2.4.1.223 — glucuronosyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase (BRENDA: 5 organisms, 17 substrates, 1 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• 3-O-(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->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl)-L-seryl-[protein] + UDP + H(+) (RHEA:16221)

UniProt features (104 total): helix 29, strand 28, binding site 12, turn 9, sequence variant 9, disulfide bond 6, glycosylation site 3, topological domain 2, chain 1, site 1, modified residue 1, transmembrane region 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8OG1	X-RAY DIFFRACTION	1.58
8OG4	X-RAY DIFFRACTION	2.1
7AU2	ELECTRON MICROSCOPY	2.43
7AUA	ELECTRON MICROSCOPY	2.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43909-F1	84.22	0.50

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 (2): 277 (not glycosylated); 833

Ligand- & substrate-binding residues (12): 728; 744; 745; 746; 746; 832; 833; 876; 668; 672; 697; 723

Post-translational modifications (1): 362

Disulfide bonds (6): 177–182, 188–236, 400–415, 793, 831–879, 915

Glycosylation sites (3): 290, 592, 790

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis
R-HSA-381038	XBP1(S) activates chaperone genes

MSigDB gene sets: 616 (showing top): MORF_RAGE, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, MORF_MSH3, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_KERATINOCYTE_PROLIFERATION, AREB6_03, MORF_BRCA1, MORF_ATRX, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, AATGGAG_MIR136, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS

GO Biological Process (15): positive regulation of keratinocyte proliferation (GO:0010838), heparan sulfate proteoglycan biosynthetic process (GO:0015012), quinolinate biosynthetic process (GO:0019805), positive regulation of cell growth (GO:0030307), response to lipopolysaccharide (GO:0032496), negative regulation of keratinocyte differentiation (GO:0045617), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), negative regulation of inflammatory response to wounding (GO:0106015), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of detection of glucose (GO:2000972), obsolete protein glycosylation (GO:0006486), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of inflammatory response (GO:0050728), inflammatory response to wounding (GO:0090594), positive regulation of cytokine production involved in inflammatory response (GO:1900017)

GO Molecular Function (8): magnesium ion binding (GO:0000287), glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity (GO:0001888), protein-hormone receptor activity (GO:0016500), glycosyltransferase activity (GO:0016757), protein binding (GO:0005515), acetylglucosaminyltransferase activity (GO:0008375), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): Golgi membrane (GO:0000139), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1
IRE1alpha activates chaperones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cytokine production involved in inflammatory response	2
regulation of cytokine production involved in inflammatory response	2
inflammatory response	2
cytoplasm	2
endomembrane system	2
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
dicarboxylic acid biosynthetic process	1
quinolinate metabolic process	1
pyridine-containing compound biosynthetic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
keratinocyte differentiation	1
negative regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
negative regulation of multicellular organismal process	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of inflammatory response	1
inflammatory response to wounding	1
regulation of inflammatory response to wounding	1
negative regulation of response to wounding	1
negative regulation of cytokine production	1
positive regulation of response to stimulus	1
detection of glucose	1
regulation of detection of glucose	1
intracellular signaling cassette	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1

Protein interactions and networks

STRING

912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXTL3	NDST1	P52848	844
EXTL3	B3GAT3	O94766	747
EXTL3	XYLT2	Q9H1B5	721
EXTL3	TRAP1	Q12931	718
EXTL3	SLC35B2	Q8TB61	704
EXTL3	HS2ST1	Q7LGA3	699
EXTL3	B4GALT7	Q9UBV7	688
EXTL3	REG3A	Q06141	654
EXTL3	XYLT1	Q86Y38	650
EXTL3	REG1A	P05451	639
EXTL3	GLCE	O94923	623
EXTL3	B3GALT6	Q96L58	618
EXTL3	CHSY1	Q86X52	616
EXTL3	NDST2	P52849	612
EXTL3	K7EP71	K7EP71	611

IntAct

134 interactions, top by confidence:

A	B	Type	Score
ADCY9	NEMP1	psi-mi:“MI:0914”(association)	0.640
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
NEMP1	RGPD8	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
EXTL3	ATXN1	psi-mi:“MI:0915”(physical association)	0.560
EXTL3		psi-mi:“MI:0915”(physical association)	0.550
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
SPPL2B	UQCRQ	psi-mi:“MI:0914”(association)	0.530
DEFA6	EXTL3	psi-mi:“MI:0914”(association)	0.530
SV2C	EXTL3	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM95	EXTL3	psi-mi:“MI:0914”(association)	0.530
WBP1	EXTL3	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
PON2	NPC1	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
ATP1A3	AGPAT2	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
SV2A	EXTL3	psi-mi:“MI:0914”(association)	0.530
EXTL3	CRK	psi-mi:“MI:0915”(physical association)	0.400
SRC	EXTL3	psi-mi:“MI:0915”(physical association)	0.400
FYN	EXTL3	psi-mi:“MI:0915”(physical association)	0.400
EXTL3	GRB2	psi-mi:“MI:0915”(physical association)	0.400
EXTL3	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (156): EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0A1H7M6, A1YGR5, A1YGR6, E9KID2, E9KID3, F4HXW9, G7LG31, O00469, O36022, O43909, O74745, P14769, P23336, P39107, P50127, P53697, P97259, Q00314, Q08834, Q09199, Q09328, Q1L8D2, Q3L7M0, Q3U4G3, Q494Q2, Q5GF25, Q5RD93, Q5SRI9, Q5ZLK4, Q6DE40, Q6NXH2, Q7YQE1, Q805R1, Q80RC7, Q811A3, Q866Z4, Q8H1E6, Q8LPF8, Q8R4G6, Q8W486

Diamond homologs: A2Y6Z7, O01705, O43909, O77783, P70428, Q53WK1, Q5IGR8, Q5RBC3, Q84WB7, Q93063, Q9WVL6, Q9XZ08, Q9Y169, Q3E9A4, Q3EAR7, Q94AA9, Q9ES89, Q9LY62, Q9UBQ6, A9X1C8, Q16394, Q6NMM8, A5D7I4, A9RGD8, O01704, P97464, Q33AH8, Q5IGR6, Q5IGR7, Q6H4N0, Q7XLG3, Q8S1X7, Q8S1X8, Q8S1X9, Q92935, Q940Q8, Q9FFN2, Q9FZJ1, Q9JK82, Q9JKV7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metal ion SLC transporters	6	35.7×	2e-06
Downstream signal transduction	6	22.6×	2e-05
R-HSA-425366	9	16.1×	2e-06
SLC-mediated transmembrane transport	12	7.0×	2e-05
Neurotransmitter receptors and postsynaptic signal transmission	6	6.0×	8e-03
Transmission across Chemical Synapses	7	5.3×	7e-03
Transport of small molecules	15	3.7×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
zinc ion transmembrane transport	8	41.6×	9e-09
intracellular zinc ion homeostasis	8	28.5×	1e-07
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	9.7×	6e-03
chemical synaptic transmission	10	5.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	281
Likely benign	279
Benign	13

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
443194	GRCh37/hg19 8p23.1-11.1(chr8:11935023-43824035)x3	Pathogenic
996966	NM_001440.4(EXTL3):c.472C>T (p.Arg158Ter)	Likely pathogenic

SpliceAI

1643 predictions. Top by Δscore:

Variant	Effect	Δscore
8:28713560:GAA:G	donor_gain	1.0000
8:28731218:CACAG:C	acceptor_loss	1.0000
8:28731219:ACAG:A	acceptor_gain	1.0000
8:28731219:ACAGG:A	acceptor_loss	1.0000
8:28731220:CA:C	acceptor_loss	1.0000
8:28731221:A:AG	acceptor_gain	1.0000
8:28731221:AG:A	acceptor_gain	1.0000
8:28731221:AGGT:A	acceptor_gain	1.0000
8:28731222:G:GG	acceptor_gain	1.0000
8:28731222:GG:G	acceptor_gain	1.0000
8:28731222:GGT:G	acceptor_gain	1.0000
8:28731222:GGTG:G	acceptor_gain	1.0000
8:28731351:G:GG	donor_gain	1.0000
8:28737516:AAG:A	acceptor_gain	1.0000
8:28737516:AAGG:A	acceptor_gain	1.0000
8:28737517:A:G	acceptor_gain	1.0000
8:28737662:AGGT:A	donor_loss	1.0000
8:28737665:T:G	donor_loss	1.0000
8:28743084:A:AG	acceptor_gain	1.0000
8:28743085:G:GG	acceptor_gain	1.0000
8:28743085:GTATT:G	acceptor_gain	1.0000
8:28743109:T:G	acceptor_gain	1.0000
8:28743111:T:TA	acceptor_gain	1.0000
8:28743212:AAGGT:A	donor_loss	1.0000
8:28743215:GTG:G	donor_loss	1.0000
8:28743216:T:G	donor_loss	1.0000
8:28750651:TTCCA:T	acceptor_loss	1.0000
8:28750652:TCCA:T	acceptor_loss	1.0000
8:28750654:CAG:C	acceptor_loss	1.0000
8:28750655:A:AT	acceptor_loss	1.0000

AlphaMissense

6017 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:28716337:T:C	L93P	1.000
8:28717293:T:A	W412R	1.000
8:28717293:T:C	W412R	1.000
8:28717295:G:C	W412C	1.000
8:28717295:G:T	W412C	1.000
8:28718047:T:C	F663S	1.000
8:28718062:T:G	L668W	1.000
8:28718074:G:C	R672P	1.000
8:28718086:T:C	L676P	1.000
8:28718134:T:A	V692D	1.000
8:28718145:T:A	W696R	1.000
8:28718145:T:C	W696R	1.000
8:28718150:T:A	N697K	1.000
8:28718150:T:G	N697K	1.000
8:28718181:T:A	W708R	1.000
8:28718181:T:C	W708R	1.000
8:28731248:T:C	L725S	1.000
8:28731248:T:G	L725W	1.000
8:28731259:T:C	F729L	1.000
8:28731260:T:C	F729S	1.000
8:28731261:C:A	F729L	1.000
8:28731261:C:G	F729L	1.000
8:28731296:T:C	L741P	1.000
8:28731304:G:C	D744H	1.000
8:28731305:A:C	D744A	1.000
8:28731305:A:G	D744G	1.000
8:28731305:A:T	D744V	1.000
8:28731306:T:A	D744E	1.000
8:28731306:T:G	D744E	1.000
8:28731307:G:C	D745H	1.000

dbSNP variants (sampled 300 via entrez): RS1000023436 (8:28698166 A>G), RS1000040091 (8:28718760 A>G), RS1000103112 (8:28637925 T>C,G), RS1000116385 (8:28661686 C>G), RS1000116723 (8:28671302 G>T), RS1000140535 (8:28740253 G>T), RS1000171303 (8:28621109 G>A,C), RS1000195606 (8:28701765 G>A,T), RS1000197850 (8:28692468 T>A), RS1000227817 (8:28615301 C>T), RS1000230923 (8:28743339 C>T), RS1000237681 (8:28614882 A>G), RS1000242254 (8:28743674 T>A,C), RS1000247546 (8:28647945 C>T), RS1000248871 (8:28731803 A>G)

Disease associations

OMIM: gene MIM:605744 | disease phenotypes: MIM:617425, MIM:600513, MIM:607174

GenCC curated gene-disease

Disease	Classification	Inheritance
immunoskeletal dysplasia with neurodevelopmental abnormalities	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunoskeletal dysplasia with neurodevelopmental abnormalities	Moderate	AR

Mondo (3): immunoskeletal dysplasia with neurodevelopmental abnormalities (MONDO:0044312), familial sleep-related hypermotor epilepsy (MONDO:0000030), familial meningioma (MONDO:0011789)

Orphanet (2): Sleep-related hypermotor epilepsy (Orphanet:98784), Familial multiple meningioma (Orphanet:263662)

HPO phenotypes

148 total (30 of 148 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000085	Horseshoe kidney
HP:0000160	Narrow mouth
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000414	Bulbous nose
HP:0000448	Prominent nose
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000498	Blepharitis
HP:0000520	Proptosis
HP:0000582	Upslanted palpebral fissure
HP:0000639	Nystagmus
HP:0000733	Motor stereotypy
HP:0000765	Abnormal thorax morphology
HP:0000767	Pectus excavatum
HP:0000924	Abnormality of the skeletal system
HP:0000926	Platyspondyly
HP:0000954	Single transverse palmar crease
HP:0000960	Sacral dimple

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002702_9	Height	2.000000e-08
GCST008179_18	Moderate-to-late spontaneous preterm birth	4.000000e-06
GCST011065_12	Levodopa-induced dyskinesia in levodopa treated Parkinson’s disease	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth
EFO:0010747	response to levodopa

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C579932	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (supp.)
C537443	Meningioma, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs352428	EXTL3	3	6.00	1	citalopram;escitalopram

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
abrine	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Genistein	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT04386642	PHASE4	UNKNOWN	Tranexamic Acid Reduce Blood Loss in Meningioma Resection
NCT06377371	PHASE4	RECRUITING	Feasibility of Intraoperative Tracing of Meningioma Using [Cu64]DOTATATE
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT03015701	PHASE3	COMPLETED	S9005 Mifepristone in Meningioma
NCT03558516	PHASE3	COMPLETED	Magnesium and Intraoperative Blood Loss in Meningioma Surgery
NCT04305470	PHASE3	COMPLETED	Gleolan for Visualization of Newly Diagnosed or Recurrent Meningioma
NCT00003483	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Meningioma
NCT00589784	PHASE2	COMPLETED	Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma
NCT00706810	PHASE2	COMPLETED	Combination of Hydroxyurea and Verapamil for Refractory Meningiomas
NCT00859040	PHASE2	COMPLETED	Monthly SOM230C for Recurrent or Progressive Meningioma
NCT01967823	PHASE2	COMPLETED	T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer
NCT02523014	PHASE2	RECRUITING	Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas
NCT02648997	PHASE2	ACTIVE_NOT_RECRUITING	An Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma
NCT02831257	PHASE2	COMPLETED	AZD2014 In NF2 Patients With Progressive or Symptomatic Meningiomas
NCT02847559	PHASE2	RECRUITING	Optune Delivered Electric Field Therapy and Bevacizumab in Treating Patients With Recurrent or Progressive Grade 2 or 3 Meningioma
NCT03013387	PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 90Y-DOTATOC
NCT03071874	PHASE2	UNKNOWN	Vistusertib (AZD2014) For Recurrent Grade II-III Meningiomas
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03273712	PHASE2	COMPLETED	Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) With 90Y-DOTA- tyr3-Octreotide (90Y-DOTATOC)
NCT03971461	PHASE2	ACTIVE_NOT_RECRUITING	Phase II Study of 177Lu-DOTATATE Radionuclide in Adults With Progressive or High-risk Meningioma
NCT04082520	PHASE2	RECRUITING	Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy
NCT04298541	PHASE2	NOT_YET_RECRUITING	Direct Comparison of Ga-68-DOTATATE and Ga-68-DOTATOC
NCT04374305	PHASE2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT04659811	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Radiosurgery and Immunotherapy (Pembrolizumab) for the Treatment of Recurrent Meningioma
NCT05425004	PHASE2	RECRUITING	Cabozantinib for Patients With Recurrent or Progressive Meningioma
NCT05940493	PHASE2	RECRUITING	Abemaciclib in Newly Diagnosed Meningioma Patients
NCT06012929	PHASE2	WITHDRAWN	A Study of ONC201 for Refractory Meningioma
NCT06126588	PHASE2	RECRUITING	Combination of Everolimus and 177Lu-DOTATATE in the Treatment of Grades 2 and 3 Refractory Meningioma: a Phase IIb Clinical Trial
NCT06132685	PHASE2	RECRUITING	Post-Operative Dosing of Dexamethasone in Patients With Brain Tumors After a Craniotomy, PODS Trial
NCT06322342	PHASE2	COMPLETED	Phase 2 Ascending Dose Safety and Efficacy Study of RVP-001, a Manganese-based MRI Contrast Agent
NCT06326190	PHASE2	RECRUITING	177Lu-DOTATATE for Recurrent Meningioma
NCT06439420	PHASE2	COMPLETED	CBT-I in Primary Brain Tumor Patients: Phase IIc Randomized Feasibility Pilot Trial
NCT06684795	PHASE2	RECRUITING	FG001 in Subjects with Meningiomas or Presumed Low-Grade Gliomas Scheduled for Neurosurgery
NCT06710249	PHASE2	RECRUITING	Impact of Salovum® and SPC® Flakes on Brain Tumor Induced Edema
NCT06804655	PHASE2	NOT_YET_RECRUITING	Pharmacoscopy for Patients With Refractory Primary Brain Tumors
NCT07428616	PHASE2	RECRUITING	A Study of Zanzalintinib in Participants With Recurrent or Progressive Meningioma
NCT07533942	PHASE2	NOT_YET_RECRUITING	A Study of JZP3507 (ONC206) in Recurrent Grade 2 or 3 Meningioma
NCT03267836	PHASE1	TERMINATED	Neoadjuvant Avelumab and Hypofractionated Proton Radiation Therapy Followed by Surgery for Recurrent Radiation-refractory Meningioma