HAPLN4

Summary

HAPLN4 (hyaluronan and proteoglycan link protein 4, HGNC:31357) is a protein-coding gene on chromosome 19p13.11, encoding Hyaluronan and proteoglycan link protein 4 (Q86UW8). Essential for the proper localization of brevican (BCAN), mainly as a perineuronal nets (PNNs)-type deposition in the brainstem and cerebellum thereby playing a key role in the formation and structural organization of PNNs.

Predicted to be a structural constituent of synapse-associated extracellular matrix. Predicted to be involved in GABAergic synaptic transmission; nervous system development; and skeletal system development. Predicted to be located in extracellular region. Predicted to be active in extracellular space; perineuronal net; and synapse.

Source: NCBI Gene 404037 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_023002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31357
Approved symbol	HAPLN4
Name	hyaluronan and proteoglycan link protein 4
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	BRAL2, KIAA1926
Ensembl gene	ENSG00000187664
Ensembl biotype	protein_coding
OMIM	619710
Entrez	404037

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000291481, ENST00000592862, ENST00000898464, ENST00000898465, ENST00000898466

RefSeq mRNA: 1 — MANE Select: NM_023002 NM_023002

CCDS: CCDS12398

Canonical transcript exons

ENST00000291481 — 5 exons

Exon	Start	End
ENSE00001182393	19254756	19258208
ENSE00001416336	19262730	19262804
ENSE00003512699	19260813	19261175
ENSE00003528916	19261446	19261563
ENSE00003644171	19258523	19258855

Expression profiles

Bgee: expression breadth ubiquitous, 101 present calls, max score 93.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8709 / max 83.7297, expressed in 123 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180133	0.6045	99
180132	0.1261	48
180134	0.0945	38
180131	0.0458	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primary visual cortex	UBERON:0002436	93.31	gold quality
superior frontal gyrus	UBERON:0002661	93.14	gold quality
right frontal lobe	UBERON:0002810	90.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.57	gold quality
frontal cortex	UBERON:0001870	88.47	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.35	gold quality
prefrontal cortex	UBERON:0000451	86.95	gold quality
cerebral cortex	UBERON:0000956	85.47	gold quality
anterior cingulate cortex	UBERON:0009835	82.34	gold quality
duodenum	UBERON:0002114	79.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.89	gold quality
hypothalamus	UBERON:0001898	78.74	gold quality
right lobe of liver	UBERON:0001114	76.43	gold quality
Ammon’s horn	UBERON:0001954	75.54	gold quality
cerebellum	UBERON:0002037	74.79	gold quality
cerebellar cortex	UBERON:0002129	74.57	gold quality
cerebellar hemisphere	UBERON:0002245	74.44	gold quality
brain	UBERON:0000955	74.06	gold quality
ventricular zone	UBERON:0003053	73.97	gold quality
cortical plate	UBERON:0005343	73.07	gold quality
substantia nigra	UBERON:0002038	71.35	gold quality
small intestine	UBERON:0002108	70.53	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.31	gold quality
ganglionic eminence	UBERON:0004023	68.67	gold quality
liver	UBERON:0002107	68.54	gold quality
temporal lobe	UBERON:0001871	67.40	gold quality
putamen	UBERON:0001874	67.28	gold quality
amygdala	UBERON:0001876	67.08	gold quality
islet of Langerhans	UBERON:0000006	66.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	64.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	11.92
E-ANND-3	no	0.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

118 targeting HAPLN4, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6739-5P	99.80	67.87	2806

Literature-anchored findings (GeneRIF, showing 1)

• 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	hapln4	ENSDARG00000018542
mus_musculus	Hapln4	ENSMUSG00000007594
rattus_norvegicus	Hapln4	ENSRNOG00000049949

Paralogs (7): VCAN (ENSG00000038427), NCAN (ENSG00000130287), BCAN (ENSG00000132692), HAPLN2 (ENSG00000132702), HAPLN3 (ENSG00000140511), HAPLN1 (ENSG00000145681), ACAN (ENSG00000157766)

Protein

Protein identifiers

Hyaluronan and proteoglycan link protein 4 — Q86UW8 (reviewed: Q86UW8)

Alternative names: Brain link protein 2

All UniProt accessions (1): Q86UW8

UniProt curated annotations — full annotation on UniProt →

Function. Essential for the proper localization of brevican (BCAN), mainly as a perineuronal nets (PNNs)-type deposition in the brainstem and cerebellum thereby playing a key role in the formation and structural organization of PNNs. Contributes to the formation and transmission of inhibitory GABAergic synapses between Purkinje cells and deep cerebellar nuclei neurons.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed predominantly in brain.

Similarity. Belongs to the HAPLN family.

RefSeq proteins (1): NP_075378* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000538	Link_dom	Domain
IPR003598	Ig_sub2	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 (11 total): disulfide bond 5, domain 3, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UW8-F1	82.32	0.63

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): 318–339, 68–143, 185–266, 209–230, 293–363

Glycosylation sites (1): 132

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 66 (showing top): GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, GOBP_SYNAPTIC_SIGNALING, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_SYNAPSE, chr19p13, GOMF_HYALURONIC_ACID_BINDING, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2

GO Biological Process (5): skeletal system development (GO:0001501), cell adhesion (GO:0007155), central nervous system development (GO:0007417), synaptic transmission, GABAergic (GO:0051932), inhibitory synapse assembly (GO:1904862)

GO Molecular Function (2): hyaluronic acid binding (GO:0005540), structural constituent of synapse-associated extracellular matrix (GO:0150043)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), 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 process	1
nervous system development	1
chemical synaptic transmission	1
synapse assembly	1
carboxylic acid binding	1
extracellular matrix structural constituent	1
synapse-associated extracellular matrix	1
cell junction	1
perisynaptic extracellular matrix	1
cellular anatomical structure	1

Protein interactions and networks

STRING

972 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAPLN4	TM6SF2	Q9BZW4	967
HAPLN4	TM6SF1	Q9BZW5	946
HAPLN4	KCNS2	Q9ULS6	633
HAPLN4	BCAN	Q96GW7	617
HAPLN4	IQCF5	A8MTL0	558
HAPLN4	PVALB	P20472	554
HAPLN4	NCAN	O14594	532
HAPLN4	CCDC183	Q5T5S1	530
HAPLN4	ADAMTS8	Q9UP79	495
HAPLN4	SCN1B	Q07699	487
HAPLN4	USP46	P62068	476
HAPLN4	C5orf58	C9J3I9	468
HAPLN4	TENM4	Q6N022	457
HAPLN4	STK32B	Q9NY57	451
HAPLN4	HAS1	Q92839	450

IntAct

0 interactions, top by confidence:

BioGRID (2): HAPLN4 (Protein-RNA), HAPLN4 (Affinity Capture-MS)

ESM2 similar proteins: A2A9Q0, A5PKD8, B0BNK7, D2HFT7, D4A2Q0, D4ABX8, E9Q7T7, O75325, P04629, P0C6S8, P0C7J6, P35739, Q04785, Q13641, Q1RMS4, Q2WF71, Q3UFB7, Q460M5, Q4R8Y9, Q50LG9, Q5PQV5, Q6GQU6, Q6IEE6, Q6IQX7, Q6NUI6, Q6PJG9, Q6UWL6, Q7M6Z0, Q80TG9, Q80WD1, Q80WM4, Q80XU8, Q86UN3, Q86UW8, Q8BHA1, Q8BLY3, Q8IZ52, Q8WX77, Q99M75, Q99PI8

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

672 predictions. Top by Δscore:

Variant	Effect	Δscore
19:19260815:T:TA	donor_gain	1.0000
19:19260828:TG:T	donor_gain	1.0000
19:19258521:AC:A	donor_gain	0.9900
19:19258522:CC:C	donor_gain	0.9900
19:19258522:CCCGG:C	donor_gain	0.9900
19:19258853:CGC:C	acceptor_gain	0.9900
19:19260773:T:TA	donor_gain	0.9900
19:19260810:CACCT:C	donor_loss	0.9900
19:19260811:ACCTT:A	donor_loss	0.9900
19:19260848:T:TA	donor_gain	0.9900
19:19261172:CCCT:C	acceptor_gain	0.9900
19:19261173:CCTC:C	acceptor_gain	0.9900
19:19261176:C:CC	acceptor_gain	0.9900
19:19262729:CCAT:C	donor_gain	0.9900
19:19258205:CGCC:C	acceptor_gain	0.9800
19:19258207:CC:C	acceptor_gain	0.9800
19:19258208:CC:C	acceptor_gain	0.9800
19:19258209:C:A	acceptor_loss	0.9800
19:19258210:T:A	acceptor_loss	0.9800
19:19258519:GCAC:G	donor_loss	0.9800
19:19258520:CACC:C	donor_loss	0.9800
19:19258521:A:C	donor_loss	0.9800
19:19258522:C:CA	donor_loss	0.9800
19:19261092:G:T	acceptor_gain	0.9800
19:19261174:CT:C	acceptor_gain	0.9800
19:19258829:C:CT	acceptor_gain	0.9700
19:19260797:C:A	donor_gain	0.9700
19:19261444:AC:A	donor_gain	0.9700
19:19261445:CC:C	donor_gain	0.9700
19:19262724:ACTT:A	donor_loss	0.9700

AlphaMissense

2537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:19258701:C:A	W213C	1.000
19:19258701:C:G	W213C	1.000
19:19258846:A:C	F165C	1.000
19:19260869:C:G	C143S	1.000
19:19260870:A:T	C143S	1.000
19:19261039:C:A	W86C	1.000
19:19261039:C:G	W86C	1.000
19:19261041:A:G	W86R	1.000
19:19261041:A:T	W86R	1.000
19:19257937:G:C	C363W	0.999
19:19258034:G:T	P331H	0.999
19:19258060:C:A	W322C	0.999
19:19258060:C:G	W322C	0.999
19:19258073:C:G	C318S	0.999
19:19258074:A:T	C318S	0.999
19:19258096:C:A	W310C	0.999
19:19258096:C:G	W310C	0.999
19:19258540:A:C	F267C	0.999
19:19258542:G:C	C266W	0.999
19:19258543:C:G	C266S	0.999
19:19258543:C:T	C266Y	0.999
19:19258544:A:G	C266R	0.999
19:19258544:A:T	C266S	0.999
19:19258546:A:C	F265C	0.999
19:19258785:G:C	C185W	0.999
19:19258786:C:T	C185Y	0.999
19:19258845:A:C	F165L	0.999
19:19258845:A:T	F165L	0.999
19:19258846:A:G	F165S	0.999
19:19258847:A:G	F165L	0.999

dbSNP variants (sampled 300 via entrez): RS1000139501 (19:19257744 G>A,T), RS1000387082 (19:19260253 G>T), RS1000441276 (19:19263751 C>T), RS1000653124 (19:19254358 C>A,T), RS1000821392 (19:19259975 A>G), RS1001048485 (19:19262197 T>C,G), RS1001315785 (19:19258230 T>A,G), RS1001608650 (19:19264219 G>A), RS1001890532 (19:19259804 A>G), RS1002214926 (19:19262612 C>T), RS1002321573 (19:19257056 C>T), RS1002448087 (19:19254323 A>G), RS1002673569 (19:19262811 G>A,T), RS1003053620 (19:19259553 T>C), RS1003391613 (19:19259255 C>T)

Disease associations

OMIM: gene MIM:619710 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002149_11	Schizophrenia	3.000000e-09
GCST002539_89	Schizophrenia	4.000000e-10
GCST006585_658	Blood protein levels	1.000000e-06
GCST006803_88	Schizophrenia	7.000000e-12
GCST008103_10	Bipolar disorder	1.000000e-09
GCST008115_2	Bipolar I disorder	3.000000e-09
GCST008116_4	Bipolar II disorder	4.000000e-06
GCST010002_52	Refractive error	4.000000e-29
GCST010703_335	Brain morphology (MOSTest)	3.000000e-10
GCST011346_39	Total cholesterol levels	7.000000e-32
GCST011347_59	Low density lipoprotein cholesterol levels	5.000000e-21
GCST011925_5	Triglyceride levels x fish oil supplementation interaction (2df)	4.000000e-53
GCST011928_2	Triglyceride levels x fish oil supplementation interaction (1df)	2.000000e-06
GCST012020_537	Serum metabolite levels	1.000000e-10
GCST90002403_286	Red blood cell count	3.000000e-15

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder
EFO:0009964	bipolar II disorder
EFO:0004346	neuroimaging measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0600007	fish oil supplement exposure measurement
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
propionaldehyde	decreases expression	1
titanium dioxide	increases expression	1
sodium arsenite	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Diethylnitrosamine	increases expression	1
Phthalic Acids	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Dronabinol	increases expression	1
Triclosan	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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