HAPLN2

Summary

HAPLN2 (hyaluronan and proteoglycan link protein 2, HGNC:17410) is a protein-coding gene on chromosome 1q23.1, encoding Hyaluronan and proteoglycan link protein 2 (Q9GZV7). Mediates a firm binding of versican V2 to hyaluronic acid. It is a selective cancer dependency (DepMap: 29.1% of cell lines).

Predicted to enable hyaluronic acid binding activity. Predicted to be involved in central nervous system development and skeletal system development. Predicted to act upstream of or within establishment of blood-nerve barrier and extracellular matrix assembly. Predicted to be located in extracellular matrix. Predicted to be active in extracellular space; perineuronal net; and synapse.

Source: NCBI Gene 60484 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• Cancer dependency (DepMap): dependent in 29.1% of screened cell lines
• MANE Select transcript: NM_021817

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17410
Approved symbol	HAPLN2
Name	hyaluronan and proteoglycan link protein 2
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	BRAL1
Ensembl gene	ENSG00000132702
Ensembl biotype	protein_coding
OMIM	619726
Entrez	60484

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000255039, ENST00000456112, ENST00000482204, ENST00000487988, ENST00000494218, ENST00000858235, ENST00000858236, ENST00000858237, ENST00000858238, ENST00000858239, ENST00000858240, ENST00000858241, ENST00000968559, ENST00000968560, ENST00000968561, ENST00000968562

RefSeq mRNA: 1 — MANE Select: NM_021817 NM_021817

CCDS: CCDS1148

Canonical transcript exons

ENST00000255039 — 7 exons

Exon	Start	End
ENSE00000904798	156623807	156624160
ENSE00001074007	156620018	156620158
ENSE00001074013	156619415	156619535
ENSE00001074014	156625101	156625725
ENSE00003473603	156624601	156624783
ENSE00003507871	156623467	156623575
ENSE00003790900	156624351	156624467

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 99.69.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.9418 / max 1114.5837, expressed in 113 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5743	6.5335	89
5744	0.6626	76
5745	0.2804	62
5746	0.2378	63
5742	0.1146	52
5749	0.0455	26
201757	0.0400	25
5747	0.0274	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.69	gold quality
spinal cord	UBERON:0002240	98.71	gold quality
putamen	UBERON:0001874	95.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.87	gold quality
amygdala	UBERON:0001876	94.63	gold quality
right frontal lobe	UBERON:0002810	94.61	gold quality
inferior vagus X ganglion	UBERON:0005363	94.58	gold quality
caudate nucleus	UBERON:0001873	94.54	gold quality
cerebellar hemisphere	UBERON:0002245	94.31	gold quality
cerebellar cortex	UBERON:0002129	94.22	gold quality
substantia nigra	UBERON:0002038	94.03	gold quality
midbrain	UBERON:0001891	93.38	gold quality
nucleus accumbens	UBERON:0001882	93.33	gold quality
inferior olivary complex	UBERON:0002127	93.08	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.04	gold quality
hypothalamus	UBERON:0001898	92.96	gold quality
cerebellum	UBERON:0002037	92.24	gold quality
anterior cingulate cortex	UBERON:0009835	91.80	gold quality
cingulate cortex	UBERON:0003027	91.78	gold quality
Ammon’s horn	UBERON:0001954	91.63	gold quality
cranial nerve II	UBERON:0000941	90.84	gold quality
corpus callosum	UBERON:0002336	90.84	gold quality
prefrontal cortex	UBERON:0000451	90.35	gold quality
subthalamic nucleus	UBERON:0001906	90.21	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.71	gold quality
telencephalon	UBERON:0001893	89.57	gold quality
frontal cortex	UBERON:0001870	88.53	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.27	gold quality
neocortex	UBERON:0001950	88.14	gold quality
temporal lobe	UBERON:0001871	88.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	645.35
E-ANND-3	no	2.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting HAPLN2, 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-137-3P	99.87	74.74	2401
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6840-5P	88.69	60.91	68

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 29.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• gene locus at chromosome 1q21-23. (PMID:11873941)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• Results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. (PMID:19633295)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hapln2	ENSDARG00000003903
mus_musculus	Hapln2	ENSMUSG00000004894
rattus_norvegicus	Hapln2	ENSRNOG00000018870

Paralogs (7): VCAN (ENSG00000038427), NCAN (ENSG00000130287), BCAN (ENSG00000132692), HAPLN3 (ENSG00000140511), HAPLN1 (ENSG00000145681), ACAN (ENSG00000157766), HAPLN4 (ENSG00000187664)

Protein

Protein identifiers

Hyaluronan and proteoglycan link protein 2 — Q9GZV7 (reviewed: Q9GZV7)

Alternative names: Brain link protein 1

All UniProt accessions (2): Q9GZV7, Q5T3J1

UniProt curated annotations — full annotation on UniProt →

Function. Mediates a firm binding of versican V2 to hyaluronic acid. May play a pivotal role in the formation of the hyaluronan-associated matrix in the central nervous system (CNS) which facilitates neuronal conduction and general structural stabilization. Binds to hyaluronic acid.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed only in adult brain.

Similarity. Belongs to the HAPLN family.

RefSeq proteins (1): NP_068589* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000538	Link_dom	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050691	Hyaluronan_bind_Proteoglycan	Family

Pfam: PF00193, PF07686

UniProt features (10 total): disulfide bond 5, domain 3, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZV7-F1	89.57	0.80

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 (5): 57–128, 170–240, 194–215, 265–336, 290–311

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 100 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, AP4_Q6, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, CAGCTG_AP4_Q5, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ENDOTHELIUM_DEVELOPMENT, HP1SITEFACTOR_Q6, TGACATY_UNKNOWN, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOCC_NEURON_PROJECTION, GOBP_PERIPHERAL_NERVOUS_SYSTEM_DEVELOPMENT, SOX5_01

GO Biological Process (5): skeletal system development (GO:0001501), cell adhesion (GO:0007155), central nervous system development (GO:0007417), establishment of blood-nerve barrier (GO:0008065), extracellular matrix assembly (GO:0085029)

GO Molecular Function (2): hyaluronic acid binding (GO:0005540), protein binding (GO:0005515)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), node of Ranvier (GO:0033268), synapse (GO:0045202), perineuronal net (GO:0072534), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
cellular anatomical structure	2
cellular process	1
nervous system development	1
endothelial cell development	1
peripheral nervous system development	1
cellular component assembly	1
extracellular matrix organization	1
carboxylic acid binding	1
binding	1
external encapsulating structure	1
main axon	1
cell junction	1
perisynaptic extracellular matrix	1

Protein interactions and networks

STRING

1264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAPLN2	NRCAM	Q92823	760
HAPLN2	PTPRZ1	P23471	739
HAPLN2	SPTBN4	Q9H254	608
HAPLN2	CNTN1	Q12860	584
HAPLN2	NFASC	O94856	581
HAPLN2	BCAN	Q96GW7	569
HAPLN2	ERMN	Q8TAM6	535
HAPLN2	GLDN	Q6ZMI3	527
HAPLN2	ANK3	Q12955	462
HAPLN2	VCAN	P13611	435
HAPLN2	CHST7	Q9NS84	433
HAPLN2	CNTNAP1	P78357	426
HAPLN2	ATP5MJ	P56378	422
HAPLN2	IQCF2	Q8IXL9	414
HAPLN2	NIPAL4	Q0D2K0	413

IntAct

138 interactions, top by confidence:

A	B	Type	Score
KRTAP2-4	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
HAPLN2	MID2	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLC	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
BANP	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT35	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT15	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
MDFI	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT40	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
TFCP2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
HAPLN2	PNMA2	psi-mi:“MI:0915”(physical association)	0.560
KRT27	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
GOLGA6L9	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
CCDC125	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT34	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT37	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
EXOSC8	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
PSTPIP1	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRT31	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
FHL5	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP9-2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (48): HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), HAPLN2 (Two-hybrid), MTUS2 (Two-hybrid)

ESM2 similar proteins: A5D8T8, O35217, O75078, O75882, O75900, O88272, O88507, O88676, O95633, P08887, P0C7M8, P0C7M9, P26992, P78539, Q00961, Q01098, Q08406, Q0ZCA7, Q14957, Q1LZB9, Q2TBM7, Q4V7F2, Q5EA46, Q5VV63, Q63769, Q642A6, Q6A051, Q6IA17, Q6P1D5, Q6PCB0, Q6UXF7, Q71DR4, Q7TNS7, Q7TSQ1, Q8NCF0, Q8R2Z5, Q8R366, Q91XD7, Q96FT7, Q96HD1

Diamond homologs: A0A182C2Z2, C6KFA3, F1RWC3, O08628, O08859, O14594, O14786, O35276, O35375, O43897, O57382, O57460, O60462, O60494, O70244, P03994, P07354, P07897, P07898, P10859, P10915, P13497, P13608, P13611, P14745, P16112, P25723, P28824, P42674, P55066, P55067, P55252, P79795, P97333, P98063, P98065, P98066, P98068, P98069, P98070

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Keratinization	15	33.4×	1e-18
Formation of the cornified envelope	9	31.6×	3e-10

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	8	76.4×	4e-12
intermediate filament organization	9	60.2×	2e-12
epithelial cell differentiation	8	39.0×	8e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1167 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156623465:AGAC:A	acceptor_gain	1.0000
1:156623466:GACG:G	acceptor_gain	1.0000
1:156624068:C:CA	acceptor_gain	1.0000
1:156624127:G:GT	donor_gain	1.0000
1:156624156:GGAGG:G	donor_gain	1.0000
1:156624157:GAGG:G	donor_gain	1.0000
1:156624157:GAGGG:G	donor_gain	1.0000
1:156624159:GG:G	donor_gain	1.0000
1:156624159:GGGT:G	donor_loss	1.0000
1:156624160:GG:G	donor_gain	1.0000
1:156624160:GGTG:G	donor_loss	1.0000
1:156624161:G:GC	donor_loss	1.0000
1:156624162:T:G	donor_loss	1.0000
1:156624780:GCGG:G	donor_gain	1.0000
1:156623465:A:AG	acceptor_gain	0.9900
1:156623466:G:GG	acceptor_gain	0.9900
1:156623466:GAC:G	acceptor_gain	0.9900
1:156623574:AGGTA:A	donor_loss	0.9900
1:156623575:GGTAA:G	donor_loss	0.9900
1:156623576:G:GA	donor_loss	0.9900
1:156623577:T:G	donor_loss	0.9900
1:156623868:T:TA	acceptor_gain	0.9900
1:156623869:G:A	acceptor_gain	0.9900
1:156624059:T:TA	acceptor_gain	0.9900
1:156624161:G:GG	donor_gain	0.9900
1:156624466:GG:G	donor_gain	0.9900
1:156624467:GG:G	donor_gain	0.9900
1:156624578:C:CA	acceptor_gain	0.9900
1:156624588:C:A	acceptor_gain	0.9900
1:156624599:A:AG	acceptor_gain	0.9900

AlphaMissense

2164 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156623929:T:A	W70R	0.999
1:156623929:T:C	W70R	0.999
1:156623931:G:C	W70C	0.999
1:156623931:G:T	W70C	0.999
1:156624103:T:A	C128S	0.999
1:156624104:G:C	C128S	0.999
1:156624360:T:G	F150C	0.999
1:156624420:G:A	C170Y	0.999
1:156624624:T:A	C194S	0.999
1:156624625:G:C	C194S	0.999
1:156624638:G:C	W198C	0.999
1:156624638:G:T	W198C	0.999
1:156624760:T:G	F239C	0.999
1:156624762:T:A	C240S	0.999
1:156624763:G:C	C240S	0.999
1:156624764:C:G	C240W	0.999
1:156625207:G:C	W282C	0.999
1:156625207:G:T	W282C	0.999
1:156624097:T:G	Y126D	0.998
1:156624359:T:C	F150L	0.998
1:156624361:T:A	F150L	0.998
1:156624361:T:G	F150L	0.998
1:156624419:T:A	C170S	0.998
1:156624420:G:C	C170S	0.998
1:156624605:G:C	W187C	0.998
1:156624605:G:T	W187C	0.998
1:156624625:G:A	C194Y	0.998
1:156624625:G:T	C194F	0.998
1:156624636:T:A	W198R	0.998
1:156624636:T:C	W198R	0.998

dbSNP variants (sampled 300 via entrez): RS1000010119 (1:156619469 C>A,T), RS1000113437 (1:156611642 C>A), RS1000243219 (1:156604581 C>G), RS1000300307 (1:156602292 A>G), RS1000333637 (1:156619104 G>A), RS1000616529 (1:156604246 C>T), RS1000923980 (1:156621071 A>C), RS1001139939 (1:156610244 TA>T), RS1001226519 (1:156602909 C>T), RS1001234390 (1:156616555 T>C), RS1001335530 (1:156623181 A>T), RS1001665989 (1:156616834 C>T), RS1001735081 (1:156610036 A>G), RS1001755372 (1:156623073 T>TA), RS1001766322 (1:156610358 C>A,T)

Disease associations

OMIM: gene MIM:619726 | disease phenotypes: MIM:123100

GenCC curated gene-disease

Mondo (1): craniosynostosis (MONDO:0015469)

Orphanet (1): Craniosynostosis (Orphanet:1531)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
sotorasib	decreases expression, affects cotreatment	1
licochalcone B	increases expression	1
bisphenol S	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Acetaminophen	decreases expression	1
Fluorouracil	affects expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Triclosan	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis