HSPG2

Summary

HSPG2 (heparan sulfate proteoglycan 2, HGNC:5273) is a protein-coding gene on chromosome 1p36.12, encoding Basement membrane-specific heparan sulfate proteoglycan core protein (P98160). Integral component of basement membranes.

This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 3339 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Schwartz-Jampel syndrome type 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 3,475 total — 62 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 250
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005529

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5273
Approved symbol	HSPG2
Name	heparan sulfate proteoglycan 2
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	perlecan, PRCAN
Ensembl gene	ENSG00000142798
Ensembl biotype	protein_coding
OMIM	142461
Entrez	3339

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 retained_intron, 5 protein_coding, 1 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000374673, ENST00000374676, ENST00000374695, ENST00000412328, ENST00000427897, ENST00000439717, ENST00000453796, ENST00000471322, ENST00000480900, ENST00000481644, ENST00000486901, ENST00000493940, ENST00000498495, ENST00000635682, ENST00000644714

RefSeq mRNA: 2 — MANE Select: NM_005529 NM_001291860, NM_005529

CCDS: CCDS30625

Canonical transcript exons

ENST00000374695 — 97 exons

Exon	Start	End
ENSE00000956520	21865717	21865809
ENSE00000956521	21865285	21865365
ENSE00000956522	21864843	21865073
ENSE00000956523	21864100	21864213
ENSE00000956524	21861988	21862115
ENSE00000956525	21861757	21861843
ENSE00000956526	21860177	21860235
ENSE00000956527	21859835	21860002
ENSE00000956528	21859566	21859676
ENSE00000956529	21857285	21857385
ENSE00000956530	21857015	21857195
ENSE00000956531	21855787	21855912
ENSE00000956532	21855523	21855675
ENSE00000956533	21855304	21855446
ENSE00000956537	21852919	21853070
ENSE00000956550	21846108	21846255
ENSE00000956552	21843297	21843438
ENSE00001043011	21887215	21887334
ENSE00001043054	21895922	21895966
ENSE00001043098	21890427	21890485
ENSE00001066249	21876229	21876405
ENSE00001066250	21885320	21885451
ENSE00001066251	21872620	21872760
ENSE00001066253	21884767	21884918
ENSE00001066254	21880107	21880254
ENSE00001066256	21876512	21876652
ENSE00001066257	21890585	21890694
ENSE00001066258	21885013	21885157
ENSE00001066259	21872997	21873091
ENSE00001066260	21878433	21878491
ENSE00001066262	21880363	21880559
ENSE00001066263	21881339	21881502
ENSE00001066264	21874406	21874533
ENSE00001066265	21874891	21875002
ENSE00001066266	21880656	21880835
ENSE00001066268	21875629	21875747
ENSE00001066269	21873925	21874011
ENSE00001066270	21878186	21878253
ENSE00001066271	21875863	21876042
ENSE00001066272	21884528	21884674
ENSE00001066273	21873375	21873424
ENSE00001066274	21878994	21879121
ENSE00001132518	21872186	21872377
ENSE00001210635	21829383	21829604
ENSE00001210640	21829993	21830091
ENSE00001210644	21830982	21831090
ENSE00001360450	21831215	21831324
ENSE00001360456	21831463	21831562
ENSE00001364411	21841539	21841673
ENSE00001364430	21842239	21842380
ENSE00001369747	21842002	21842142
ENSE00001371652	21839822	21840017
ENSE00001373155	21836802	21837006
ENSE00001376743	21831652	21831796
ENSE00001381747	21841101	21841285
ENSE00001382220	21832495	21832606
ENSE00001384698	21833816	21833925
ENSE00001385989	21833268	21833384
ENSE00001386724	21834679	21834945
ENSE00001389172	21835540	21835637
ENSE00001390016	21838825	21839085
ENSE00001390183	21839371	21839550
ENSE00001420182	21896175	21896310
ENSE00001464439	21937155	21937310
ENSE00001793002	21844148	21844299
ENSE00001799882	21842770	21842921
ENSE00003476238	21824537	21824615
ENSE00003476738	21889981	21890141
ENSE00003485756	21833467	21833614
ENSE00003492191	21848643	21848794
ENSE00003513698	21824704	21824779
ENSE00003516192	21822244	21823488
ENSE00003517062	21854193	21854343
ENSE00003522613	21878577	21878663
ENSE00003528320	21823616	21823719
ENSE00003531600	21846448	21846599
ENSE00003536652	21828255	21828426
ENSE00003549379	21854848	21854983
ENSE00003555121	21854611	21854765
ENSE00003564236	21828835	21829079
ENSE00003569001	21847354	21847492
ENSE00003570735	21827863	21827919
ENSE00003573238	21824306	21824376
ENSE00003574658	21848893	21849031
ENSE00003578054	21847958	21848093
ENSE00003583788	21824121	21824204
ENSE00003590276	21850363	21850498
ENSE00003590429	21887420	21887674
ENSE00003604966	21887938	21888066
ENSE00003620847	21851546	21851697
ENSE00003630085	21851791	21851926
ENSE00003638886	21828030	21828152
ENSE00003639789	21852088	21852233
ENSE00003648889	21850041	21850192
ENSE00003653312	21874616	21874729
ENSE00003676672	21847689	21847840
ENSE00003689584	21852700	21852832

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 99.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 76.1637 / max 1706.4187, expressed in 1583 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10900	74.9077	1579
10899	0.7038	396
10890	0.2424	128
10881	0.2084	97
10886	0.0789	30
10879	0.0225	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.38	gold quality
popliteal artery	UBERON:0002250	99.28	gold quality
tibial artery	UBERON:0007610	99.27	gold quality
aorta	UBERON:0000947	99.25	gold quality
thoracic aorta	UBERON:0001515	99.23	gold quality
descending thoracic aorta	UBERON:0002345	99.23	gold quality
ascending aorta	UBERON:0001496	99.22	gold quality
right coronary artery	UBERON:0001625	99.22	gold quality
tibial nerve	UBERON:0001323	99.18	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.17	gold quality
lower esophagus	UBERON:0013473	99.16	gold quality
coronary artery	UBERON:0001621	99.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.06	gold quality
left coronary artery	UBERON:0001626	99.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.03	gold quality
right atrium auricular region	UBERON:0006631	98.99	gold quality
body of uterus	UBERON:0009853	98.98	gold quality
apex of heart	UBERON:0002098	98.96	gold quality
left uterine tube	UBERON:0001303	98.91	gold quality
sural nerve	UBERON:0015488	98.83	gold quality
omental fat pad	UBERON:0010414	98.79	gold quality
peritoneum	UBERON:0002358	98.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.73	gold quality
cardiac atrium	UBERON:0002081	98.72	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.66	gold quality
myometrium	UBERON:0001296	98.64	gold quality
olfactory bulb	UBERON:0002264	98.51	gold quality
blood vessel layer	UBERON:0004797	98.51	gold quality
right lobe of thyroid gland	UBERON:0001119	98.49	gold quality
fundus of stomach	UBERON:0001160	98.44	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	2196.21
E-MTAB-6701	yes	1940.85
E-MTAB-8410	yes	1540.37
E-MTAB-9906	yes	1113.76
E-HCAD-11	yes	954.23
E-MTAB-8205	yes	405.33
E-MTAB-10553	yes	53.06
E-HCAD-10	yes	44.70
E-HCAD-1	yes	40.20
E-GEOD-135922	yes	39.31
E-CURD-46	yes	35.09
E-HCAD-9	yes	20.12
E-MTAB-6678	yes	17.65
E-CURD-112	yes	11.16
E-MTAB-9067	yes	8.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FBLN1, FN1, STAT1

miRNA regulators (miRDB)

43 targeting HSPG2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6848-5P	98.81	65.49	1126

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia (PMID:11941538)
• Augmented synthesis and differential localization of heparan sulfate proteoglycans in Duchenne muscular dystrophy. (PMID:11968010)
• Identification of integrin alpha(M)beta(2) as an adhesion receptor on human peripheral blood monocytes for Cyr61 and connective tissue growth factor: immediate-early gene products expressed in atherosclerotic lesions.(integrin alpha(M)beta(2)) (PMID:12036876)
• CTGF/Hcs24 produced in the hypertrophic region may act on chondrocytes in the proliferative and maturative zone via some heparan sulfate proteoglycan, such as perlecan. (PMID:12811819)
• progranulin/perlecan interactions have a role in the fine regulation of tumor angiogenesis (PMID:12900424)
• expression of perlecan, but not other HSPGs, is dramatically down-regulated in human umbilical vein endothelial cells (HUVECs) treated with antiangiogenic cleaved and latent forms of antithrombin but not with the native form. (PMID:14563633)
• HSPG2 A allele may possess an additive risk effect in APOE epsilon 4 carriers in a Finnish population with Alzheimer’s disease. (PMID:14625044)
• results demonstrate that extracellular matrix perlecan is a degradative target of heparanase (HPSE-1) (PMID:14630925)
• increased expression associated with Cyclosporin A-induced gingival overgrowth (PMID:14974815)
• Hyperglycemia-induced structural changes in perlecan may result in a subendothelial matrix that is more favorable to retention of monocytes. (PMID:15031130)
• findings show no evidence for association between HSPG2 intron 6 BamHI polymorphism and Alzheimer’s disease in a Jewish population, and no interactive effect was found with the known risk factor apolipoprotein E (APOE) epsilon4. (PMID:15211644)
• Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin (PMID:15240572)
• We conclude that the perlecan mediates Tat uptake and is required for HIV-1 LTR-directed transactivation in WiDr cells. (PMID:15567441)
• High affinity interactions between fibrillin-1 and perlecan were found by kinetic binding studies with dissociation constants in the low nanomolar range. (PMID:15657057)
• The gene expression of perlecan is partially suppressed by antiangiogenic forms of antithrombin. (PMID:15905187)
• Results describe perlecan purified from HEK-293 cells substituted with heparan sulphate, chondroitin sulphate and keratan sulphate; first to report perlecan containing keratan sulphate (PMID:16129435)
• perlecan regulates both the survival and terminal differentiation steps of keratinocytes (PMID:16269412)
• Perlecan is an essential extracellular matrix component involved in growth responses of metastatic prostate cancer cells to heparin-binding growth factors deposited in local and metastatic microenvironment (PMID:16283481)
• WARP forms macromolecular structures that interact with perlecan to contribute to the assembly and/or maintenance of “permanent” cartilage structures during development and in mature cartilages (PMID:16407285)
• The expression level of perlecan and perlecan mRNA significantly increased in Hep-2 cells as compared with normal cells. (PMID:16570819)
• Reduction of perlecan mRNA-expression and protein deposition in human atherosclerosis, which in part explains the low levels of heparan sulfate in this disease. (PMID:16620836)
• perlecan secreted by VEGF165-stimulated endothelial cells may be involved in the regulation of cellular behavior during angiogenesis (PMID:16914267)
• perlecan is a prominent pericellular proteoglycan differently expressed in fetal, postnatal, and mature hyaline cartilage (PMID:16984910)
• The HSPG2 BamH I polymorphism C/A of intron 6 may not represent an additional genetic risk factor for late-onset AD. (PMID:17356275)
• the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the alpha2beta1 integrin receptor. (PMID:18024432)
• Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis. (PMID:18658137)
• TT genotype showed significantly increased risk for urolithiasis than TG and GG genotypes. (PMID:19066875)
• Examine association between perlecan SNPs and intracranial aneurysms in Japanese cohort. (PMID:19506372)
• the angioinhibitory action of NK4 involves impaired extracellular assembly of fibronectin mediated by perlecan-NK4 association (PMID:19553700)
• The perlecan was prominently immunolocalised in the cartilaginous vertebral body rudiments and to a lesser extent within the foetal intervertebral disc. (PMID:19669783)
• These data highlight the potential role of perlecan oxidation, and consequent deregulation of cell function, in vascular injuries by myeloperoxidase-derived hypochlorous and hypobromous acids. (PMID:19788922)
• Endorepellin caused a widespread reduction in phosphorylation of key receptors involved in angiogenesis & a concurrent increase in phosphatase activity in endothelial cells & tumor xenografts. (PMID:19789387)
• there might be no association between perlecan gene polymorphism and spinal muscular atrophy type I disease. (PMID:19839757)
• in contrast to IA, HSPG2 and CSPG2 do not associate with AAA. (PMID:20053631)
• These findings suggest that the HSPG2 gene is involved in neuroleptic-induced tardive dyskinesia (TD) and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility. (PMID:20072119)
• perlecan plays an indispensible role in endothelial cell proliferation and acts through a mechanism that involves subcellular localization of p27. (PMID:20074558)
• FGF2 and -18 bind to discrete structures on the heparan sulfate chains attached to chondrocyte-derived perlecan which modulate the growth factor activities (PMID:20507176)
• perlecan followed virtually identical immunolocalisation pattern to type II collagen in foetal joint tissue, but a slightly divergent pattern in adult tissues; evidence indicates perlecan is a marker of chondrogenic cells in prenatal cartilages (PMID:20690028)
• Domain V of perlecan, a known alpha2 integrin ligand, inhibits brain amyloid-beta neurotoxicity in an alpha2 integrin-dependent manner. (PMID:21126803)
• Ameloblastoma cells proliferate and are differentiated by capturing perlecan differentially with alpha-dystroglycan and integrin beta1, respectively (PMID:21255062)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hspg2	ENSDARG00000076564
mus_musculus	Hspg2	ENSMUSG00000028763
rattus_norvegicus	Hspg2	ENSRNOG00000021437
drosophila_melanogaster	trol	FBGN0284408

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), LAMC2 (ENSG00000058085), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF8 (ENSG00000105429), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), TMEFF2 (ENSG00000144339), NTN3 (ENSG00000162068), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878), TMEFF1 (ENSG00000241697)

Protein

Protein identifiers

Basement membrane-specific heparan sulfate proteoglycan core protein — P98160 (reviewed: P98160)

Alternative names: Perlecan

All UniProt accessions (6): P98160, A0A0U1RQT3, A0A2R8YH07, A0A3B3IT11, H0Y5A9, H7BYA5

UniProt curated annotations — full annotation on UniProt →

Function. Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development. In muscle, it is essential for localizing acetylcholinesterase (AChE) at the neuromuscular junctions (NMJ), most probably acting as an adapter that links the acetylcholinesterase collagenic tail peptide (COLQ) to alpha-dystroglycan, and is therefore involved in the down-regulation of colinergic synaptic transmission. Anti-angiogenic and anti-tumor peptide that inhibits endothelial cell migration, collagen-induced endothelial tube morphogenesis and blood vessel growth in the chorioallantoic membrane. Blocks endothelial cell adhesion to fibronectin and type I collagen. Anti-tumor agent in neovascularization. Interaction with its ligand, integrin alpha2/beta1, is required for the anti-angiogenic properties. Evokes a reduction in phosphorylation of receptor tyrosine kinases via alpha2/beta1 integrin-mediated activation of the tyrosine phosphatase, PTPN6. Has anti-angiogenic properties that require binding of calcium ions for full activity.

Subunit / interactions. Has a strong tendency to aggregate in dimers or stellate structures. Interacts with other basement membrane components such as laminin, prolargin and collagen type IV. Interacts with COL13A1. Interacts with FGFBP1. Interacts with VWA1. Interacts (via C-terminus) with ECM1 (via C-terminus). Interacts with SVEP1. Interacts (via C-terminus) with alpha-dystroglycan; the interaction is required for acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ). Interacts with the acetylcholinesterase collagenic tail peptide (COLQ).

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane.

Tissue specificity. Detected in cerebrospinal fluid, fibroblasts and urine (at protein level).

Post-translational modifications. Proteolytic processing produces the C-terminal angiogenic peptide, endorepellin. This peptide can be further processed to produce the LG3 peptide. O-glycosylated with core 1 or possibly core 8 glycans. Contains three heparan sulfate chains. Also contains chondroitin sulfate.

Disease relevance. Schwartz-Jampel syndrome (SJS1) [MIM:255800] Rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses. The disease is caused by variants affecting the gene represented in this entry. Dyssegmental dysplasia Silverman-Handmaker type (DDSH) [MIM:224410] The dyssegmental dysplasias are rare, autosomal recessive skeletal dysplasias with anisospondyly and micromelia. There are two recognized types: the severe, lethal DDSH and the milder Rolland-Desbuquois form. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocoele. The endochondral growth plate is short, the calcospherites (which are spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Has been found in the urine of patients with end-stage renal disease and in the amniotic fluid of pregnant women with premature rupture of fetal membranes.

RefSeq proteins (2): NP_001278789, NP_005520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000034	Laminin_IV	Domain
IPR000082	SEA_dom	Domain
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002049	LE_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013106	Ig_V-set	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR023415	LDLR_class-A_CS	Conserved_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051170	Neural/epithelial_adhesion	Family
IPR056863	LMN_ATRN_NET-like_EGF	Domain

Pfam: PF00008, PF00052, PF00053, PF00054, PF00057, PF07679, PF13895, PF13927, PF24973

UniProt features (211 total): disulfide bond 58, domain 51, sequence conflict 27, sequence variant 20, glycosylation site 18, strand 15, region of interest 4, binding site 4, chain 3, mutagenesis site 3, turn 3, helix 2, signal peptide 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3SH4	X-RAY DIFFRACTION	1.5
3SH5	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

No AlphaFold model available for P98160 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (1): 4196–4197 (cleavage; by bmp1)

Ligand- & substrate-binding residues (4): 4258; 4275; 4325; 4327

Disulfide bonds (58): 816–839, 842–851, 854–869, 879–892, 894–903, 906–921, 1159–1168, 1161–1175, 1178–1187, 1190–1206, 1209–1224, 1211–1234, 1237–1246, 1249–1263, 1275–1287, 1277–1293, 1295–1304, 1307–1322, 1563–1572, 1565–1579 …

Glycosylation sites (18): 42, 65, 71, 76, 89, 554, 1755, 2121, 2995, 3072, 3105, 3279, 3780, 3836, 3933, 4068, 4179, 4193

Mutagenesis-validated functional residues (3):

Position	Phenotype
4197	abolishes bmp1-mediated cleavage of endorepellin.
4258	retains proper folding. reduced calcium ion binding.
4327	retains proper folding. reduced calcium ion binding.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1971475	Glycosaminoglycan-protein linkage region biosynthesis
R-HSA-2022928	HS-GAG biosynthesis
R-HSA-2024096	HS-GAG degradation
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000157	Laminin interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-3560783	Defective B4GALT7 causes EDS, progeroid type
R-HSA-3560801	Defective B3GAT3 causes JDSSDHD
R-HSA-3656237	Defective EXT2 causes exostoses 2
R-HSA-3656253	Defective EXT1 causes exostoses 1, TRPS2 and CHDS
R-HSA-4420332	Defective B3GALT6 causes EDSP2 and SEMDJL1
R-HSA-9694614	Attachment and Entry
R-HSA-975634	Retinoid metabolism and transport
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-977225	Amyloid fiber formation
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry
R-HSA-9833110	RSV-host interactions
R-HSA-9856532	Mechanical load activates signaling by PIEZO1 and integrins in osteocytes
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9918485	Dengue Virus Attachment and Entry

MSigDB gene sets: 775 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_52, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_INFLAMMATORY_RESPONSE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_SYNAPTIC_TRANSMISSION_CHOLINERGIC, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, RODRIGUES_NTN1_TARGETS_DN, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, MODULE_118

GO Biological Process (19): angiogenesis (GO:0001525), response to hypoxia (GO:0001666), positive regulation of endothelial cell proliferation (GO:0001938), lipid metabolic process (GO:0006629), receptor-mediated endocytosis (GO:0006898), inflammatory response (GO:0006954), negative regulation of cell adhesion (GO:0007162), smoothened signaling pathway (GO:0007224), brain development (GO:0007420), embryo implantation (GO:0007566), negative regulation of cell population proliferation (GO:0008285), response to xenobiotic stimulus (GO:0009410), negative regulation of angiogenesis (GO:0016525), cell differentiation (GO:0030154), animal organ regeneration (GO:0031100), negative regulation of synaptic transmission, cholinergic (GO:0032223), protein localization to synapse (GO:0035418), circulatory system development (GO:0072359), vesicle-mediated transport (GO:0016192)

GO Molecular Function (8): amyloid-beta binding (GO:0001540), calcium ion binding (GO:0005509), extracellular matrix structural constituent conferring compression resistance (GO:0030021), low-density lipoprotein particle receptor binding (GO:0050750), molecular adaptor activity (GO:0060090), collagen V binding (GO:0070052), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (16): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), focal adhesion (GO:0005925), extracellular matrix (GO:0031012), neuromuscular junction (GO:0031594), neuron projection (GO:0043005), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), plasma membrane protein complex (GO:0098797), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Extracellular matrix organization	5
Diseases associated with glycosaminoglycan metabolism	5
Heparan sulfate/heparin (HS-GAG) metabolism	2
Coagulation pathway	2
Respiratory Syncytial Virus Infection Pathway	2
Glycosaminoglycan metabolism	1
Early SARS-CoV-2 Infection Events	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
negative regulation of cellular process	2
animal organ development	2
binding	2
plasma membrane	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
primary metabolic process	1
endocytosis	1
defense response	1
cell adhesion	1
regulation of cell adhesion	1
cell surface receptor signaling pathway	1
central nervous system development	1
head development	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
cell population proliferation	1
regulation of cell population proliferation	1
response to chemical	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cellular developmental process	1
regeneration	1
synaptic transmission, cholinergic	1
regulation of synaptic transmission, cholinergic	1
negative regulation of synaptic transmission	1
protein localization to cell junction	1
system development	1
transport	1
cellular process	1
peptide binding	1
metal ion binding	1

Protein interactions and networks

STRING

2268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPG2	NID1	P14543	999
HSPG2	NID2	Q14112	997
HSPG2	DAG1	Q14118	996
HSPG2	FGF2	P09038	995
HSPG2	FN1	P02751	995
HSPG2	BGN	P13247	994
HSPG2	AGRN	O00468	988
HSPG2	FGF7	P21781	987
HSPG2	FBLN2	P98095	985
HSPG2	DCN	P07585	972
HSPG2	FGF18	O76093	970
HSPG2	FGF13	Q92913	966
HSPG2	FGF4	P08620	948
HSPG2	FGF20	Q9NP95	948
HSPG2	FGF22	Q9HCT0	948
HSPG2	FGF6	P10767	948
HSPG2	FGF16	O43320	948

IntAct

97 interactions, top by confidence:

A	B	Type	Score
HSPG2	KDR	psi-mi:“MI:0407”(direct interaction)	0.720
KDR	HSPG2	psi-mi:“MI:0407”(direct interaction)	0.720
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
HSPG2	FGF1	psi-mi:“MI:0915”(physical association)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
TULP3	HSPG2	psi-mi:“MI:0914”(association)	0.530
GAA	CLGN	psi-mi:“MI:0914”(association)	0.530
HSPG2	GRN	psi-mi:“MI:0915”(physical association)	0.530
HSPG2	GRN	psi-mi:“MI:0914”(association)	0.530
GRN	HSPG2	psi-mi:“MI:0915”(physical association)	0.530
HSPG2	Npnt	psi-mi:“MI:0407”(direct interaction)	0.440
FLT1	HSPG2	psi-mi:“MI:0407”(direct interaction)	0.440
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
HSPG2	FGF2	psi-mi:“MI:0915”(physical association)	0.400
CACNA1A	HSPG2	psi-mi:“MI:0915”(physical association)	0.370
Shoc2	GABPB1	psi-mi:“MI:0914”(association)	0.350
PTTG1	PMS1	psi-mi:“MI:0914”(association)	0.350
TMPO		psi-mi:“MI:0914”(association)	0.350
Pxdc1	CASK	psi-mi:“MI:0914”(association)	0.350
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.350

BioGRID (98): HSPG2 (Affinity Capture-MS), HSPG2 (Co-fractionation), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS), HSPG2 (Affinity Capture-MS)

ESM2 similar proteins: A0A131MBU3, A1Z877, B5DFC9, G5EFD5, M9PE65, O02466, O18016, O76840, O77469, O88322, O97827, P10493, P13508, P14543, P14585, P35443, P41950, P41990, P49744, P49746, P51559, P98160, Q04833, Q05793, Q05895, Q06441, Q06561, Q17800, Q19617, Q1L8P7, Q20911, Q24247, Q27591, Q29RU4, Q3SWW8, Q6DI48, Q7QIQ6, Q80TS3, Q811M5, Q8JGW0

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, B8JI71, G3I6Z6, O35516, O75882, P07207, P0DPK3, P0DPK4, P10040, P21783, P46530, P46531, P98160, Q01705, Q04721, Q04756, Q07008, Q20911, Q7Z3S9, Q99466, Q99J86, Q9QW30, Q9UM47, Q9WU60, A0A0R4IGV4, P57087, Q05793, Q1WIM1, Q2WGK2, Q8NFZ8, Q8R464, Q925F2, Q9JI59, Q9XT56, Q9Y624, A2AR95, A2ARV4, A4IHY6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HSPG2	up-regulates	PTPRS	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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
Constitutive Signaling by Aberrant PI3K in Cancer	5	8.3×	6e-03
Metabolism of carbohydrates and carbohydrate derivatives	5	7.9×	7e-03
PIP3 activates AKT signaling	8	7.0×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
fibroblast growth factor receptor signaling pathway	5	13.9×	5e-03
positive regulation of angiogenesis	8	9.0×	8e-04
positive regulation of cell migration	9	5.4×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BLCA.

Clinical variants and AI predictions

ClinVar

3475 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	46
Uncertain significance	1623
Likely benign	1090
Benign	233

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034182	NM_005529.7(HSPG2):c.12900-2A>C	Pathogenic
1069490	NM_005529.7(HSPG2):c.4765G>T (p.Glu1589Ter)	Pathogenic
1177407	NM_005529.7(HSPG2):c.3518del (p.Gly1173fs)	Pathogenic
1323076	NM_005529.7(HSPG2):c.4956-1G>A	Pathogenic
1323077	NM_005529.7(HSPG2):c.253C>T (p.Arg85Ter)	Pathogenic
1323079	NM_005529.7(HSPG2):c.5696G>A (p.Trp1899Ter)	Pathogenic
1323080	NM_005529.7(HSPG2):c.2658del (p.Thr887fs)	Pathogenic
1364613	NM_005529.7(HSPG2):c.11322_11328dup (p.Ala3777Ter)	Pathogenic
1393444	NM_005529.7(HSPG2):c.5449C>T (p.Arg1817Ter)	Pathogenic
1403044	NM_005529.7(HSPG2):c.4736_4739dup (p.Gln1581fs)	Pathogenic
1453692	NM_005529.7(HSPG2):c.9670G>T (p.Glu3224Ter)	Pathogenic
1459023	NM_005529.7(HSPG2):c.1861G>T (p.Glu621Ter)	Pathogenic
14917	NM_005529.7(HSPG2):c.8464+4A>G	Pathogenic
14918	NM_005529.7(HSPG2):c.4595G>A (p.Cys1532Tyr)	Pathogenic
14919	HSPG2, 89-BP DUP, EX34	Pathogenic
14920	NM_005529.7(HSPG2):c.6724+5G>A	Pathogenic
14921	HSPG2, 10328C-T	Pathogenic
14922	NM_005529.7(HSPG2):c.7294+4A>G	Pathogenic
14923	HSPG2, EX60/61 FUSION	Pathogenic
14924	NM_005529.7(HSPG2):c.8464G>A (p.Ala2822Thr)	Pathogenic
14925	NM_005529.7(HSPG2):c.8759-3_8764del	Pathogenic
14926	NC_000001.11:g.21816592_21823699del	Pathogenic
1879079	NM_005529.7(HSPG2):c.12393T>A (p.Cys4131Ter)	Pathogenic
2002264	NM_005529.7(HSPG2):c.3456C>G (p.Tyr1152Ter)	Pathogenic
2023431	NM_005529.7(HSPG2):c.1653_1654insT (p.Gly552fs)	Pathogenic
2047443	NM_005529.7(HSPG2):c.11750C>A (p.Ser3917Ter)	Pathogenic
2047447	NM_005529.7(HSPG2):c.740_741del (p.Leu247fs)	Pathogenic
2684225	NM_005529.7(HSPG2):c.7874-2A>G	Pathogenic
2699028	NM_005529.7(HSPG2):c.11066del (p.Lys3689fs)	Pathogenic
2710437	NM_005529.7(HSPG2):c.4245dup (p.Arg1416fs)	Pathogenic

SpliceAI

15344 predictions. Top by Δscore:

Variant	Effect	Δscore
1:21823611:CTTA:C	donor_loss	1.0000
1:21823612:TTA:T	donor_loss	1.0000
1:21823613:TA:T	donor_loss	1.0000
1:21823614:A:AC	donor_gain	1.0000
1:21823615:C:CC	donor_gain	1.0000
1:21823615:CCGAT:C	donor_gain	1.0000
1:21823716:CTCC:C	acceptor_gain	1.0000
1:21823717:TCC:T	acceptor_gain	1.0000
1:21823718:CC:C	acceptor_gain	1.0000
1:21823718:CCC:C	acceptor_gain	1.0000
1:21823719:CC:C	acceptor_gain	1.0000
1:21823720:C:CC	acceptor_gain	1.0000
1:21823720:CT:C	acceptor_loss	1.0000
1:21824301:CCTA:C	donor_loss	1.0000
1:21824302:CTA:C	donor_loss	1.0000
1:21824303:TA:T	donor_loss	1.0000
1:21824304:A:AC	donor_gain	1.0000
1:21824305:C:CC	donor_gain	1.0000
1:21824381:C:CT	acceptor_gain	1.0000
1:21824530:CA:C	donor_gain	1.0000
1:21824534:CACCA:C	donor_loss	1.0000
1:21824535:A:AC	donor_gain	1.0000
1:21824535:A:T	donor_loss	1.0000
1:21824536:C:CC	donor_gain	1.0000
1:21824536:CCA:C	donor_gain	1.0000
1:21824536:CCACA:C	donor_gain	1.0000
1:21824611:GCAGG:G	acceptor_gain	1.0000
1:21824612:CAGG:C	acceptor_gain	1.0000
1:21824612:CAGGC:C	acceptor_gain	1.0000
1:21824613:AGG:A	acceptor_gain	1.0000

AlphaMissense

28341 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:21855334:C:A	W1989C	1.000
1:21855334:C:G	W1989C	1.000
1:21857172:C:A	W1806C	1.000
1:21857172:C:G	W1806C	1.000
1:21857174:A:G	W1806R	1.000
1:21857174:A:T	W1806R	1.000
1:21842027:C:A	W3056C	0.999
1:21842027:C:G	W3056C	0.999
1:21842029:A:G	W3056R	0.999
1:21842029:A:T	W3056R	0.999
1:21848038:T:C	Y2598C	0.999
1:21848679:C:A	W2567C	0.999
1:21848679:C:G	W2567C	0.999
1:21848681:A:G	W2567R	0.999
1:21848681:A:T	W2567R	0.999
1:21855336:A:G	W1989R	0.999
1:21855336:A:T	W1989R	0.999
1:21857058:G:C	N1844K	0.999
1:21857058:G:T	N1844K	0.999
1:21857070:G:C	C1840W	0.999
1:21857071:C:G	C1840S	0.999
1:21857071:C:T	C1840Y	0.999
1:21857072:A:G	C1840R	0.999
1:21857072:A:T	C1840S	0.999
1:21857116:A:G	L1825P	0.999
1:21857300:G:C	C1793W	0.999
1:21857301:C:T	C1793Y	0.999
1:21857302:A:G	C1793R	0.999
1:21859887:C:A	W1710C	0.999
1:21859887:C:G	W1710C	0.999

dbSNP variants (sampled 300 via entrez): RS1000035048 (1:21837707 G>A,T), RS1000052372 (1:21881047 T>G), RS1000087359 (1:21825178 G>C), RS1000090250 (1:21875222 C>T), RS1000184748 (1:21857562 C>T), RS1000185751 (1:21926460 G>A), RS1000201420 (1:21889738 T>C), RS1000211845 (1:21849725 G>A,T), RS1000213207 (1:21921328 T>C), RS1000263419 (1:21886561 A>C,G), RS1000266210 (1:21912801 G>A), RS1000284445 (1:21862796 C>T), RS1000323533 (1:21870630 C>T), RS1000324865 (1:21843558 G>A,T), RS1000339741 (1:21854998 A>G,T)

Disease associations

OMIM: gene MIM:142461 | disease phenotypes: MIM:224410, MIM:255800, MIM:601559, MIM:607872

GenCC curated gene-disease

Disease	Classification	Inheritance
Silverman-Handmaker type dyssegmental dysplasia	Definitive	Autosomal recessive
Schwartz-Jampel syndrome type 1	Definitive	Autosomal recessive
Schwartz-Jampel syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Schwartz-Jampel syndrome type 1	Definitive	AR
Silverman-Handmaker type dyssegmental dysplasia	Definitive	AR

Mondo (11): Silverman-Handmaker type dyssegmental dysplasia (MONDO:0009140), Schwartz-Jampel syndrome type 1 (MONDO:0100435), Schwartz-Jampel syndrome (MONDO:0009717), connective tissue disorder (MONDO:0003900), neuromuscular disease caused by qualitative or quantitative defects of perlecan (MONDO:0016151), intellectual disability (MONDO:0001071), childhood-onset schizophrenia (MONDO:0957430), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), microcephaly (MONDO:0001149), Stuve-Wiedemann syndrome (MONDO:0031280), chromosome 1p36 deletion syndrome (MONDO:0011929)

Orphanet (8): Dyssegmental dysplasia, Silverman-Handmaker type (Orphanet:1865), Schwartz-Jampel syndrome (Orphanet:800), Qualitative or quantitative defects of perlecan (Orphanet:207101), Childhood-onset schizophrenia (Orphanet:641496), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), Stüve-Wiedemann syndrome (Orphanet:3206), 1p36 deletion syndrome (Orphanet:1606), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

250 total (30 of 250 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000055	Abnormal female external genitalia morphology
HP:0000069	Abnormality of the ureter
HP:0000077	Abnormality of the kidney
HP:0000079	Abnormality of the urinary system
HP:0000107	Renal cyst
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000205	Pursed lips
HP:0000211	Trismus
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000298	Mask-like facies
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000343	Long philtrum

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006414_101	Atrial fibrillation	2.000000e-10
GCST008163_199	Height	2.000000e-07
GCST010320_33	PR interval	3.000000e-08
GCST010321_170	PR interval	2.000000e-10
GCST011706_1	Cerebral microbleeds (lobar)	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0010059	cerebral microbleeds

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C535362	Chromosome 1p36 Deletion Syndrome (supp.)
C537998	Dyssegmental dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465297 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2445142	Toxicity	3	antipsychotics	Schizophrenia
rs878949	Toxicity	3	antipsychotics	Schizophrenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs878949	HSPG2	3	2.00	1	antipsychotics
rs2445142	HSPG2	3	2.50	1	antipsychotics

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	increases expression, affects methylation	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
Smoke	decreases expression, increases abundance	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
polyhexamethyleneguanidine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5318895	Binding	Inhibition of HSPG2 transcriptional activation in human KMS-11 cells assessed as reduction in HSPG2 mRNA expression at 0.5 uM by qRT-PCR analysis	Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7XM	Abcam Raji HSPG2 KO	Cancer cell line	Male
CVCL_B9YB	Abcam THP-1 HSPG2 KO	Cancer cell line	Male
CVCL_C7A4	Abcam PC-3 HSPG2 KO	Cancer cell line	Male
CVCL_D9GH	Ubigene HEK293 HSPG2 KO	Transformed cell line	Female
CVCL_SR81	HAP1 HSPG2 (-) 1	Cancer cell line	Male
CVCL_SR82	HAP1 HSPG2 (-) 2	Cancer cell line	Male
CVCL_SR83	HAP1 HSPG2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities