HYAL4

Summary

HYAL4 (hyaluronidase 4, HGNC:5323) is a protein-coding gene on chromosome 7q31.32, encoding Hyaluronidase-4 (Q2M3T9). Endo-hyaluronidase that degrades hyaluronan to smaller oligosaccharide fragments.

This gene encodes a protein which is similar in structure to hyaluronidases but lacks hyaluronidase activity. The encoded protein acts as a chondroitin-sulfate-specific endo-beta-N-acetylgalactosaminidase; that is, it exhibits hydrolytic activity toward chondroitin sulfate chains and degrades them into oligosaccharides. Proteoglycans are formed by the covalent linkage of chondroitin sulfate chains to protein. Proteoglycans are ubiquitous components of the extracellular matrix of connective tissues and are also found at the surface of many cell types where they participate in a variety of cellular processes such as cell proliferation, differentiation, migration, cell-cell recognition, extracellular matrix deposition, and tissue morphogenesis. The expression of this gene is highest in testes and placenta.

Source: NCBI Gene 23553 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_012269

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5323
Approved symbol	HYAL4
Name	hyaluronidase 4
Location	7q31.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106302
Ensembl biotype	protein_coding
OMIM	604510
Entrez	23553

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 nonsense_mediated_decay

ENST00000223026, ENST00000476325, ENST00000483878, ENST00000488323, ENST00000489978, ENST00000955054, ENST00000955055, ENST00000955056

RefSeq mRNA: 1 — MANE Select: NM_012269 NM_012269

CCDS: CCDS5789

Canonical transcript exons

ENST00000223026 — 5 exons

Exon	Start	End
ENSE00000719992	123874761	123874850
ENSE00000882055	123868223	123869227
ENSE00000882056	123876754	123877481
ENSE00001514966	123848089	123848158
ENSE00001514968	123845169	123845685

Expression profiles

Bgee: expression breadth broad, 93 present calls, max score 84.60.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.35	gold quality
triceps brachii	UBERON:0001509	74.24	gold quality
diaphragm	UBERON:0001103	71.02	gold quality
gastrocnemius	UBERON:0001388	70.88	gold quality
placenta	UBERON:0001987	69.71	gold quality
muscle of leg	UBERON:0001383	69.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	68.79	silver quality
muscle organ	UBERON:0001630	68.77	gold quality
skeletal muscle tissue	UBERON:0001134	68.09	gold quality
gluteal muscle	UBERON:0002000	68.08	silver quality
vastus lateralis	UBERON:0001379	67.84	silver quality
olfactory bulb	UBERON:0002264	67.75	gold quality
type B pancreatic cell	CL:0000169	67.46	gold quality
quadriceps femoris	UBERON:0001377	66.94	silver quality
thymus	UBERON:0002370	65.75	gold quality
cardia of stomach	UBERON:0001162	65.49	gold quality
trachea	UBERON:0003126	64.82	gold quality
layer of synovial tissue	UBERON:0007616	64.62	gold quality
inferior vagus X ganglion	UBERON:0005363	64.58	gold quality
dorsal plus ventral thalamus	UBERON:0001897	64.54	gold quality
saphenous vein	UBERON:0007318	64.51	gold quality
deltoid	UBERON:0001476	64.42	silver quality
muscle tissue	UBERON:0002385	64.41	gold quality
pericardium	UBERON:0002407	64.36	gold quality
penis	UBERON:0000989	64.31	silver quality
subthalamic nucleus	UBERON:0001906	64.14	gold quality
nipple	UBERON:0002030	64.11	gold quality
ventral tegmental area	UBERON:0002691	64.04	gold quality
superior surface of tongue	UBERON:0007371	63.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	172.80
E-ANND-3	yes	3.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting HYAL4, 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-3924	100.00	72.09	2394
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-3612	99.45	66.02	1333

Literature-anchored findings (GeneRIF, showing 3)

• Identification of human hyaluronidase-4 as a novel chondroitin sulfate hydrolase that preferentially cleaves the galactosaminidic linkage in the trisulfated tetrasaccharide sequence (PMID:19889881)
• Identification of amino acid residues required for the substrate specificity of human and mouse chondroitin sulfate hydrolase (conventional hyaluronidase-4). (PMID:23086929)
• A Novel Splice Variant of HYAL-4 Drives Malignant Transformation and Predicts Outcome in Patients with Bladder Cancer. (PMID:32094233)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hyal4	ENSDARG00000051823
mus_musculus	Hyal4	ENSMUSG00000029680
rattus_norvegicus	Hyal4	ENSRNOG00000007212
caenorhabditis_elegans		WBGENE00011923

Paralogs (4): HYAL2 (ENSG00000068001), SPAM1 (ENSG00000106304), HYAL1 (ENSG00000114378), HYAL3 (ENSG00000186792)

Protein

Protein identifiers

Hyaluronidase-4 — Q2M3T9 (reviewed: Q2M3T9)

Alternative names: Chondroitin sulfate endo-beta-N-acetylgalactosaminidase, Chondroitin sulfate hydrolase, Hyaluronoglucosaminidase-4

All UniProt accessions (4): Q2M3T9, C9J6F9, C9JU18, F8WDH9

UniProt curated annotations — full annotation on UniProt →

Function. Endo-hyaluronidase that degrades hyaluronan to smaller oligosaccharide fragments. Also has chondroitin sulfate hydrolase activity, The best substrate being the galactosaminidic linkage in the sequence of a trisulfated tetrasaccharide.

Subcellular location. Membrane.

Tissue specificity. Detected in placenta and skeletal muscle.

Similarity. Belongs to the glycosyl hydrolase 56 family.

RefSeq proteins (1): NP_036401* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR018155	Hyaluronidase	Family

Pfam: PF01630

Enzyme classification (BRENDA):

• EC 3.2.1.35 — hyaluronoglucosaminidase (BRENDA: 70 organisms, 156 substrates, 263 inhibitors, 27 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HYALURONAN	0.038–0.367	11
CHONDROITIN	0.12	1
CHONDROITIN SULFATE	0.48	1
CHONDROITIN SULFATE A	0.66	1
CHONDROITIN SULFATE C	2.16	1
CHONDROITIN SULFATE D	0.5	1
HYALURONIC ACID	0.0009	1
HYALURONIC ACID FROM STREPTOCOCCUS PYOGENES (35	49.3	1

UniProt features (18 total): disulfide bond 5, glycosylation site 4, topological domain 3, transmembrane region 2, chain 1, sequence variant 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M3T9-F1	91.01	0.85

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): 147 (proton donor)

Disulfide bonds (5): 59–351, 223–237, 376–387, 381–435, 437–446

Glycosylation sites (4): 343, 86, 115, 177

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2024101	CS/DS degradation
R-HSA-2160916	Hyaluronan degradation

MSigDB gene sets: 81 (showing top): GOBP_HYALURONAN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_HYALURONAN_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_CHONDROITIN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, SHEN_SMARCA2_TARGETS_DN, REACTOME_METABOLISM_OF_CARBOHYDRATES_AND_CARBOHYDRATE_DERIVATIVES, GOCC_LYSOSOMAL_LUMEN

GO Biological Process (4): carbohydrate metabolic process (GO:0005975), glycosaminoglycan catabolic process (GO:0006027), chondroitin sulfate proteoglycan catabolic process (GO:0030207), hyaluronan catabolic process (GO:0030214)

GO Molecular Function (5): hyalurononglucosaminidase activity (GO:0004415), chondroitin hydrolase activity (GO:0052757), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (5): lysosome (GO:0005764), cell surface (GO:0009986), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), lysosomal lumen (GO:0043202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chondroitin sulfate/dermatan sulfate metabolism	1
Hyaluronan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
primary metabolic process	1
aminoglycan catabolic process	1
glycosaminoglycan metabolic process	1
proteoglycan catabolic process	1
chondroitin sulfate proteoglycan metabolic process	1
glycosaminoglycan catabolic process	1
hyaluronan metabolic process	1
hexosaminidase activity	1
endogalactosaminidase activity	1
binding	1
catalytic activity	1
hydrolase activity	1
lytic vacuole	1
cytoplasm	1
intracellular vesicle	1
lysosome	1
vacuolar lumen	1

Protein interactions and networks

STRING

1517 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HYAL4	GRM8	O00222	681
HYAL4	HAS2	Q92819	590
HYAL4	CFTR	P13569	557
HYAL4	CD44	P16070	476
HYAL4	HAS3	O00219	469
HYAL4	HAS1	Q92839	410
HYAL4	HMMR	O75330	367
HYAL4	TEX101	Q9BY14	364
HYAL4	ACAN	P16112	361
HYAL4	ZP4	Q12836	353
HYAL4	EQTN	Q9NQ60	353
HYAL4	PPP1R26	Q5T8A7	351
HYAL4	ACE2	Q9BYF1	349
HYAL4	PATE4	P0C8F1	348
HYAL4	CD47	Q08722	348

IntAct

4 interactions, top by confidence:

A	B	Type	Score
HYAL4	GAPDHS	psi-mi:“MI:0915”(physical association)	0.560
HYAL4	GAPDHS	psi-mi:“MI:0914”(association)	0.560
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): HYAL4 (Co-fractionation), HYAL4 (Synthetic Growth Defect), GAPDHS (Affinity Capture-MS), HYAL4 (Affinity Capture-MS), SPCS1 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS)

ESM2 similar proteins: A2RSQ1, A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, C0HLL4, C0HLL5, E0XKJ9, E3W9M2, G5ECE8, I0CME7, I0CME8, J3S820, O22585, P23613, P38566, P38567, P38568, P48794, P49370, P49371, P49713, P58781, P85841, P86100, P86687, P86875, Q05A56, Q08169, Q10916, Q2M3T9, Q2QSR8, Q2VQV9, Q5D7H4, Q5RC46, Q60V90, Q62803

Diamond homologs: A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, B3EWP2, C0HLL4, C0HLL5, E0XKJ9, G5ECE8, I0CME8, J3S820, O35632, O43820, P23613, P38566, P38567, P38568, P48794, P49370, P49371, P85841, P86100, P86687, P86875, Q05A56, Q08169, Q12794, Q12891, Q2M3T9, Q5D7H4, Q5E985, Q5REQ1, Q62803, Q6RHW2, Q6RHW4, Q76HM9, Q76HN1

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	66
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1011 predictions. Top by Δscore:

Variant	Effect	Δscore
7:123848082:C:CA	acceptor_gain	0.9900
7:123848154:CAAAG:C	donor_loss	0.9900
7:123848155:AAAG:A	donor_loss	0.9900
7:123848156:AAGG:A	donor_loss	0.9900
7:123848157:AGGTA:A	donor_loss	0.9900
7:123848158:GGTAA:G	donor_loss	0.9900
7:123848159:G:GA	donor_loss	0.9900
7:123848160:T:A	donor_loss	0.9900
7:123848087:A:AG	acceptor_gain	0.9800
7:123848088:G:GG	acceptor_gain	0.9800
7:123848088:GGAC:G	acceptor_gain	0.9800
7:123874760:GCAA:G	acceptor_gain	0.9800
7:123848082:C:G	acceptor_gain	0.9700
7:123848083:GCACA:G	acceptor_loss	0.9700
7:123848084:CACA:C	acceptor_loss	0.9700
7:123848088:G:GA	acceptor_loss	0.9700
7:123849397:TTC:T	donor_gain	0.9700
7:123868277:A:T	donor_gain	0.9600
7:123848071:T:TA	acceptor_loss	0.9500
7:123874759:A:AG	acceptor_gain	0.9500
7:123874760:G:GG	acceptor_gain	0.9500
7:123848085:ACAG:A	acceptor_gain	0.9400
7:123845372:C:G	donor_gain	0.9300
7:123848081:AC:A	acceptor_gain	0.9300
7:123869223:CTAAG:C	donor_loss	0.9300
7:123869224:TAAG:T	donor_loss	0.9300
7:123869225:AAGGT:A	donor_loss	0.9300
7:123869226:AGGTA:A	donor_loss	0.9300
7:123869227:GG:G	donor_loss	0.9300
7:123869228:GT:G	donor_loss	0.9300

AlphaMissense

3152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:123868916:T:A	W215R	0.993
7:123868916:T:C	W215R	0.993
7:123869027:T:A	W252R	0.991
7:123869027:T:C	W252R	0.991
7:123876868:T:A	C387S	0.989
7:123876869:G:C	C387S	0.989
7:123868844:T:C	F191L	0.988
7:123868846:T:A	F191L	0.988
7:123868846:T:G	F191L	0.988
7:123874788:A:C	S328R	0.988
7:123874790:T:A	S328R	0.988
7:123874790:T:G	S328R	0.988
7:123868427:T:A	W52R	0.986
7:123868427:T:C	W52R	0.986
7:123868918:G:C	W215C	0.986
7:123868918:G:T	W215C	0.986
7:123869036:A:C	S255R	0.986
7:123869038:T:A	S255R	0.986
7:123869038:T:G	S255R	0.986
7:123876850:T:A	C381S	0.986
7:123876851:G:C	C381S	0.986
7:123869021:T:A	W250R	0.984
7:123869021:T:C	W250R	0.984
7:123868701:T:A	V143D	0.983
7:123868730:T:A	W153R	0.983
7:123868730:T:C	W153R	0.983
7:123869029:G:C	W252C	0.983
7:123869029:G:T	W252C	0.983
7:123868709:T:A	W146R	0.981
7:123868709:T:C	W146R	0.981

dbSNP variants (sampled 300 via entrez): RS1000008666 (7:123869468 C>G,T), RS1000029655 (7:123772975 A>T), RS1000069034 (7:123825448 C>A,G,T), RS1000069644 (7:123778827 A>T), RS1000132227 (7:123838761 C>T), RS1000174601 (7:123763129 A>G), RS1000177655 (7:123797831 T>C), RS1000223130 (7:123803989 A>G), RS1000322976 (7:123805254 C>T), RS1000334204 (7:123804967 C>T), RS1000380403 (7:123847488 A>G), RS1000474356 (7:123855992 G>A), RS1000480320 (7:123811954 G>A), RS1000484337 (7:123825122 C>A,T), RS1000484651 (7:123855499 C>A,G,T)

Disease associations

OMIM: gene MIM:604510 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1622	Metabolite levels	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010379	phosphatidylcholine 36:1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
testosterone enanthate	affects expression	1
sodium arsenite	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Phenobarbital	affects expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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