HYAL1

Summary

HYAL1 (hyaluronidase 1, HGNC:5320) is a protein-coding gene on chromosome 3p21.31, encoding Hyaluronidase-1 (Q12794). May have a role in promoting tumor progression.

This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3373 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 9 (Definitive, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 450 total — 29 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• MANE Select transcript: NM_033159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5320
Approved symbol	HYAL1
Name	hyaluronidase 1
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	LUCA1, HYAL-1
Ensembl gene	ENSG00000114378
Ensembl biotype	protein_coding
OMIM	607071
Entrez	3373

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 17 protein_coding

ENST00000266031, ENST00000320295, ENST00000395143, ENST00000395144, ENST00000418723, ENST00000447605, ENST00000452672, ENST00000457214, ENST00000618175, ENST00000907772, ENST00000907773, ENST00000907774, ENST00000907775, ENST00000907776, ENST00000907777, ENST00000907778, ENST00000907779

RefSeq mRNA: 5 — MANE Select: NM_033159 NM_033159, NM_153281, NM_153282, NM_153283, NM_153285

CCDS: CCDS2816, CCDS2817, CCDS46832, CCDS46833

Canonical transcript exons

ENST00000395144 — 4 exons

Exon	Start	End
ENSE00000768861	50300988	50301077
ENSE00001520714	50302057	50302980
ENSE00001676829	50303466	50303574
ENSE00001914240	50299893	50300800

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 97.69.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3733 / max 177.9587, expressed in 576 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42311	2.3619	575
42310	0.0114	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.69	gold quality
liver	UBERON:0002107	97.04	gold quality
spleen	UBERON:0002106	96.00	gold quality
apex of heart	UBERON:0002098	95.91	gold quality
heart left ventricle	UBERON:0002084	94.23	gold quality
adult mammalian kidney	UBERON:0000082	94.08	gold quality
right lung	UBERON:0002167	93.84	gold quality
metanephros cortex	UBERON:0010533	91.32	gold quality
upper lobe of left lung	UBERON:0008952	89.56	gold quality
kidney	UBERON:0002113	89.05	gold quality
heart	UBERON:0000948	88.35	gold quality
cortex of kidney	UBERON:0001225	88.20	gold quality
right adrenal gland	UBERON:0001233	87.83	gold quality
right adrenal gland cortex	UBERON:0035827	87.20	gold quality
left adrenal gland	UBERON:0001234	86.91	gold quality
left adrenal gland cortex	UBERON:0035825	86.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.23	gold quality
lung	UBERON:0002048	85.91	gold quality
right atrium auricular region	UBERON:0006631	85.57	gold quality
skin of leg	UBERON:0001511	85.28	gold quality
adrenal gland	UBERON:0002369	84.47	gold quality
zone of skin	UBERON:0000014	84.45	gold quality
body of stomach	UBERON:0001161	84.45	gold quality
gall bladder	UBERON:0002110	84.13	gold quality
skin of abdomen	UBERON:0001416	83.56	gold quality
stomach	UBERON:0000945	81.88	gold quality
fundus of stomach	UBERON:0001160	81.20	gold quality
ectocervix	UBERON:0012249	81.16	gold quality
muscle of leg	UBERON:0001383	80.71	gold quality
skeletal muscle organ	UBERON:0014892	80.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP7, EGR1, ESR1, HAS3, NFKB1, PDGFB, PGR, RELA, SP1

miRNA regulators (miRDB)

24 targeting HYAL1, 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-4666B	99.64	68.69	1282
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-4289	98.26	66.90	810
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-597-3P	96.46	68.03	1035
HSA-MIR-6806-5P	96.37	68.74	587
HSA-MIR-203A-5P	96.33	65.03	714
HSA-MIR-591	96.29	68.16	611
HSA-MIR-103B	95.51	66.85	441

Literature-anchored findings (GeneRIF, showing 40)

• Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3. (PMID:11929860)
• Alternative mRNA splicing controls cellular expression of enzymatically active hyaluronidase. (PMID:12084718)
• Down-regulation of HYAL1 is associated with small cell lung cancer and glioma (PMID:12684632)
• Increased expression of hyaluronidase is associated with head and neck tumors (PMID:12845686)
• Hyaluronidase and CD44 hyaluronan receptor are expressed in squamous cell laryngeal carcinoma (PMID:16713680)
• Gene silencing of HYAL1 inhibited cell proliferation and induced cell cycle arrest in human breast cancer cells. (PMID:16831275)
• HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G(2)-M phase and increased apoptosis. (PMID:17145867)
• Purified recombinant Hyal-1 from Drosophila cells was used for the investigation of the inhibitory activity of new ascorbic acid derivatives (PMID:17227790)
• further support to altered glycosaminoglycan metabolism (hyaluronan and hyaluronidase blood levels)in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis. (PMID:17415544)
• hyaluronan processing by elevated HYAL1 expression in invasive prostate cancer is a requirement for progression. (PMID:17502371)
• crystal structure reveals a molecule composed of two closely associated domains: a catalytic domain that adopts a distorted (beta/alpha)8 barrel resembling that of bee venom hyaluronidase, and a novel, EGF-like domain (PMID:17503783)
• Hyaluronidase activity is modulated by complexing with various polyelectrolytes including hyaluronan (PMID:18083358)
• The expression of HYAL1 in ductal hyperplastic tissues is a strong predictor of subsequent development of invasive breast cancer (PMID:18281563)
• Bovine serum albumin competes with human hyalurinodase and thus increases hyaluronidase release resulting in a large increase in the hydrolysis rate. (PMID:18677769)
• HYAL-1 expression is epigenetically regulated by the binding of different transcription factors to the methylated and unmethylated HYAL-1 promoter (PMID:18718911)
• Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer (PMID:19140316)
• define key components of Hyal1 active site catalysis, and structural factors critical for stability (PMID:19201751)
• HYAL-1 is a potential prognostic marker for predicting progression to muscle invasion and recurrence in bladder cancer. (PMID:19345473)
• HYAL1, but not HYAL2, expression is reduced and correlates with the accumulation of hyaluronan in ovarian carcinomas. (PMID:19435493)
• Data showed that the HYAL1 variant exhibited hyaluronan degradation at elevated pH. (PMID:19478093)
• Invasive features of ER(-) breast cancer cells can be characterized in vitro by higher secretion of hyaluronidase, higher expression of proteinases MMP-9, cath-D, and the angiogenesis promoting factor VEGF. (PMID:19567141)
• Data show that a significant in expression levels of HA synthases (HASs) and hyaluronidases (Hyals) was observed in vitro on stimulation of epithelial ovarian carcinoma cells by gonadotropins. (PMID:20072653)
• HYAL1 overexpression is correlated with the malignant behavior of breast cancer. (PMID:20473947)
• The protein products HABP2 and HYAL1 were associated with plasma PAI-1 concentration and play key roles in hyaluronan metabolism, providing genetic evidence to link these pathways. (PMID:20558613)
• rhHyal-1 is endocytosed by the liver. (PMID:20572808)
• Overexpression of HYAL1 is associated with colorectal cancer. (PMID:20849597)
• Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma (PMID:20875124)
• HYAL-1 and HAS1 expression predicted BCa metastasis, and HYAL-1 expression also predicted disease-specific survival. (PMID:20960509)
• In contrast to the previously described MPS IX patient, our three patients display a phenotype limited to the joints, suggesting that this is the primary manifestation of HYAL1 deficiency. (PMID:21559944)
• This is the first report showing high HYAL-1 levels in epithelial ovarian cancer. (PMID:21695196)
• Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels. (PMID:23166824)
• Results demonstrated that HYAL1 was C-mannosylated and suggest the possible role of C-mannosylation for secretion and enzymatic activity of HYAL1. (PMID:24820161)
• Study showed that reduced HYAL1 expression was associated with endometrial carcinoma aggressiveness, which further supported the role of hyaluronan degradation in cancer progression. (PMID:25584766)
• The receiver-operating characteristic curve analyses demonstrated that each one had good sensitivity and specificity for distinguishing BC patients from non-BC ones (HYAL1, miR-210, miR-96, lncRNA-UCA1, 91.5 and ). (PMID:26138586)
• HAS2 and HAS3 were the only hyaluronan synthases detected, the expression of which was almost similar in NPs and NM. (PMID:26661071)
• Molecular docking simulation explains the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. (PMID:27424109)
• Data revealed a significant inverse correlation between ERalpha and HYAL1 gene expression in human breast tumors. HYAL1 was found repressed by estrogen through ERalpha binding to a consensus response element (ERE) located in the proximal promoter of HYAL1 and flanked by an Sp1 binding site, required to achieve optimal estrogen repression. (PMID:27764788)
• Ureaplasma urealyticum infection may affect the activity of hyaluronidase on spermatozoa (PMID:28012250)
• our results suggest that the enzyme HYAL1 plays a role in tumor dissemination and brain-specific colonization, rather than in subsequent metastatic out-growth. (PMID:28168629)
• The presence of Hyal1 in tumor-derived exosomes and its ability to impact the behavior of stromal cells suggests cell-cell communication via exosomes is a novel mechanism by which elevated Hyal1 promotes prostate cancer progression. (PMID:29753676)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hyal1	ENSDARG00000059916
mus_musculus	Hyal1	ENSMUSG00000010051
rattus_norvegicus	Hyal1	ENSRNOG00000015858
caenorhabditis_elegans		WBGENE00011923

Paralogs (4): HYAL2 (ENSG00000068001), HYAL4 (ENSG00000106302), SPAM1 (ENSG00000106304), HYAL3 (ENSG00000186792)

Protein

Protein identifiers

Hyaluronidase-1 — Q12794 (reviewed: Q12794)

Alternative names: Hyaluronoglucosaminidase-1, Lung carcinoma protein 1

All UniProt accessions (5): A0A024R2X3, A0A0S2Z3Q0, C9JB49, C9JRK1, Q12794

UniProt curated annotations — full annotation on UniProt →

Function. May have a role in promoting tumor progression. May block the TGFB1-enhanced cell growth.

Subcellular location. Secreted. Lysosome.

Tissue specificity. Highly expressed in the liver, kidney and heart. Weakly expressed in lung, placenta and skeletal muscle. No expression detected in adult brain. Isoform 1 is expressed only in bladder and prostate cancer cells, G2/G3 bladder tumor tissues and lymph node specimens showing tumor invasive tumors cells. Isoform 3, isoform 4, isoform 5 and isoform 6 are expressed in normal bladder and bladder tumor tissues.

Disease relevance. Mucopolysaccharidosis 9 (MPS9) [MIM:601492] A form of mucopolysaccharidosis, a group of lysosomal storage diseases characterized by defective degradation of glycosaminoglycans, resulting in their excessive accumulation and secretion. The diseases are progressive and often display a wide spectrum of clinical severity. MPS9 is an autosomal recessive form characterized by high hyaluronan concentration in the serum. Clinical features include periarticular soft tissue masses, mild short stature and acetabular erosions, and absence of neurological or visceral involvement. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Enzymatically inactive. Enzymatically inactive. Enzymatically inactive. Enzymatically inactive. Enzymatically inactive.

Similarity. Belongs to the glycosyl hydrolase 56 family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q12794-1	1	yes
Q12794-2	2, HYAl1v1
Q12794-3	3, HYAl1v2
Q12794-4	4, HYAl1v3
Q12794-5	5, HYAl1v4
Q12794-6	6, HYAl1v5
Q12794-7	7

RefSeq proteins (5): NP_149349, NP_695013, NP_695014, NP_695015, NP_695017 (=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)
• EC 4.2.2.1 — hyaluronate lyase (BRENDA: 69 organisms, 109 substrates, 155 inhibitors, 24 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HYALURONAN	0.038–0.367	11
HYALURONAN	0.0006–3.8	9
HYALURONIC ACID	0.285–0.71	4
HYALURONATE	0.38–0.44	2
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
HYALURONAN HEXASACCHARIDE	0.08	1

UniProt features (59 total): helix 18, strand 15, splice variant 8, disulfide bond 5, sequence conflict 3, glycosylation site 3, turn 2, signal peptide 1, chain 1, domain 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2PE4	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12794-F1	94.18	0.90

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): 131 (proton donor)

Disulfide bonds (5): 363–418, 420–429, 43–333, 207–221, 358–369

Glycosylation sites (3): 99, 216, 350

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2024101	CS/DS degradation
R-HSA-2160916	Hyaluronan degradation
R-HSA-2206280	MPS IX - Natowicz syndrome (Hyaluronan metabolism)
R-HSA-9953097	MPS IX - Natowicz syndrome (CS/DS degradation)

MSigDB gene sets: 226 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_GROWTH, GOBP_HYALURONAN_CATABOLIC_PROCESS

GO Biological Process (22): response to reactive oxygen species (GO:0000302), carbohydrate metabolic process (GO:0005975), inflammatory response (GO:0006954), response to virus (GO:0009615), chondroitin sulfate proteoglycan catabolic process (GO:0030207), hyaluronan metabolic process (GO:0030212), hyaluronan catabolic process (GO:0030214), positive regulation of cell growth (GO:0030307), negative regulation of cell growth (GO:0030308), cellular response to platelet-derived growth factor stimulus (GO:0036120), cellular response to fibroblast growth factor stimulus (GO:0044344), positive regulation of angiogenesis (GO:0045766), positive regulation of cell adhesion (GO:0045785), response to antibiotic (GO:0046677), cartilage development (GO:0051216), embryonic skeletal joint morphogenesis (GO:0060272), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to pH (GO:0071467), cellular response to UV-B (GO:0071493), positive regulation of hyaluranon cable assembly (GO:1900106), glycosaminoglycan catabolic process (GO:0006027)

GO Molecular Function (4): hyalurononglucosaminidase activity (GO:0004415), chondroitin hydrolase activity (GO:0052757), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), lysosome (GO:0005764), cytoplasmic vesicle (GO:0031410), hyaluranon cable (GO:0036117), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mucopolysaccharidoses	2
Chondroitin sulfate/dermatan sulfate metabolism	1
Hyaluronan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cell growth	2
cell growth	2
positive regulation of cellular process	2
cellular response to growth factor stimulus	2
cellular response to cytokine stimulus	2
cellular anatomical structure	2
response to oxidative stress	1
response to oxygen-containing compound	1
primary metabolic process	1
defense response	1
response to other organism	1
proteoglycan catabolic process	1
chondroitin sulfate proteoglycan metabolic process	1
glycosaminoglycan metabolic process	1
glycosaminoglycan catabolic process	1
hyaluronan metabolic process	1
positive regulation of growth	1
negative regulation of growth	1
negative regulation of cellular process	1
response to platelet-derived growth factor	1
response to fibroblast growth factor	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
cell adhesion	1
regulation of cell adhesion	1
response to chemical	1
skeletal system development	1
animal organ development	1
connective tissue development	1
embryonic skeletal system morphogenesis	1
embryonic skeletal joint development	1
response to interleukin-1	1
response to tumor necrosis factor	1
response to pH	1
cellular response to abiotic stimulus	1
response to UV-B	1
cellular response to UV	1
hexosaminidase activity	1
endogalactosaminidase activity	1

Protein interactions and networks

STRING

1913 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HYAL1	HAS2	Q92819	823
HYAL1	CD44	P16070	749
HYAL1	HAS1	Q92839	725
HYAL1	HAS3	O00219	656
HYAL1	CEMIP	Q8WUJ3	623
HYAL1	HMMR	O75330	620
HYAL1	MST1R	Q04912	586
HYAL1	NPRL2	Q8WTW4	547
HYAL1	CEMIP2	Q9UHN6	534
HYAL1	SEMA3F	Q13275	492
HYAL1	HABP2	Q14520	488
HYAL1	RASSF1	Q9NS23	480
HYAL1	GALNS	P34059	474
HYAL1	HGSNAT	Q68CP4	472
HYAL1	IDUA	P35475	455

IntAct

10 interactions, top by confidence:

A	B	Type	Score
HYAL1	COL2A1	psi-mi:“MI:0915”(physical association)	0.370
HYAL1	CANX	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
ELSPBP1	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
GGH	MANBA	psi-mi:“MI:0914”(association)	0.350
HYAL1	CDIPT	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): HYAL1 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), TUBA1B (Affinity Capture-MS), HYAL1 (Positive Genetic), UBR2 (Affinity Capture-MS), CANX (Affinity Capture-MS), HYAL1 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HYAL1 (Affinity Capture-MS), GGT7 (Affinity Capture-MS), ACAD10 (Affinity Capture-MS)

ESM2 similar proteins: A0JND9, E1BPW0, O14773, O18956, O35795, O55026, O75173, O75355, O75356, O75578, O89023, O93295, P08514, P08648, P11688, P17405, P49961, P55772, P56201, P79784, P97687, Q04519, Q0VD19, Q12794, Q32M88, Q49HH9, Q49KI5, Q5DRK1, Q5IS74, Q5MY95, Q5RFL1, Q5RFQ8, Q60HH1, Q6P3E7, Q6P6S9, Q717C1, Q717C2, Q7RTX0, Q8BFW6, Q8BNJ2

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

3 interactions.

A	Effect	B	Mechanism
EGR1	“up-regulates quantity by expression”	HYAL1	“transcriptional regulation”
SP1	“down-regulates quantity by repression”	HYAL1	“transcriptional regulation”
NfKb-p65/p50	“up-regulates quantity by expression”	HYAL1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	15
Uncertain significance	161
Likely benign	194
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072055	NM_033159.4(HYAL1):c.707G>A (p.Trp236Ter)	Pathogenic
1073037	NM_033159.4(HYAL1):c.787C>T (p.Gln263Ter)	Pathogenic
1074510	NM_033159.4(HYAL1):c.691del (p.Gln231fs)	Pathogenic
1342863	NM_033159.4(HYAL1):c.104del (p.Val35fs)	Pathogenic
1365687	NM_033159.4(HYAL1):c.521_524dup (p.Phe175fs)	Pathogenic
1452834	NM_033159.4(HYAL1):c.937C>T (p.Gln313Ter)	Pathogenic
1458685	NC_000003.11:g.(?50338409)(50341042_?)del	Pathogenic
2018303	NM_033159.4(HYAL1):c.410G>A (p.Trp137Ter)	Pathogenic
2023599	NM_033159.4(HYAL1):c.597G>A (p.Trp199Ter)	Pathogenic
2052431	NM_033159.4(HYAL1):c.4del (p.Ala2fs)	Pathogenic
2062762	NM_033159.4(HYAL1):c.345_348dup (p.Ile117fs)	Pathogenic
2115682	NM_033159.4(HYAL1):c.440del (p.Tyr147fs)	Pathogenic
2427429	NC_000003.11:g.(?50340112)(50342638_?)del	Pathogenic
2695909	NM_033159.4(HYAL1):c.250del (p.Tyr84fs)	Pathogenic
2745132	NM_033159.4(HYAL1):c.268del (p.Glu90fs)	Pathogenic
2780854	NM_033159.4(HYAL1):c.658C>T (p.Gln220Ter)	Pathogenic
2817930	NM_033159.4(HYAL1):c.545G>A (p.Trp182Ter)	Pathogenic
2849597	NM_033159.4(HYAL1):c.599del (p.Gly200fs)	Pathogenic
2849832	NM_033159.4(HYAL1):c.190C>T (p.Gln64Ter)	Pathogenic
2866304	NM_033159.4(HYAL1):c.775C>T (p.Gln259Ter)	Pathogenic
3016878	NM_033159.4(HYAL1):c.85_88dup (p.Arg30fs)	Pathogenic
3531	NM_033159.4(HYAL1):c.751_787delinsTTCCGTGTGGCCCG (p.Val251fs)	Pathogenic
3643413	NM_033159.4(HYAL1):c.39del (p.Thr14fs)	Pathogenic
4717664	NM_033159.4(HYAL1):c.33_34del (p.Phe12fs)	Pathogenic
643652	NM_033159.4(HYAL1):c.133G>T (p.Glu45Ter)	Pathogenic
830555	NC_000003.11:g.(?50339478)(50341042_?)del	Pathogenic
941180	NM_033159.4(HYAL1):c.441C>G (p.Tyr147Ter)	Pathogenic
951930	NM_033159.4(HYAL1):c.44del (p.Leu15fs)	Pathogenic
963698	NM_033159.4(HYAL1):c.621C>A (p.Cys207Ter)	Pathogenic
2021178	NM_033159.4(HYAL1):c.900+1G>A	Likely pathogenic

SpliceAI

632 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50302052:CTCA:C	donor_loss	1.0000
3:50302053:TCA:T	donor_loss	1.0000
3:50302054:CA:C	donor_loss	1.0000
3:50302056:C:CT	donor_loss	1.0000
3:50300798:TTC:T	acceptor_gain	0.9900
3:50300801:C:CC	acceptor_gain	0.9900
3:50300801:CTA:C	acceptor_loss	0.9900
3:50300802:T:C	acceptor_loss	0.9900
3:50300983:CTCA:C	donor_loss	0.9900
3:50300984:TCAC:T	donor_loss	0.9900
3:50300985:CA:C	donor_loss	0.9900
3:50300986:A:AG	donor_loss	0.9900
3:50301143:CAT:C	acceptor_gain	0.9900
3:50302049:AGACT:A	donor_loss	0.9900
3:50302050:GACTC:G	donor_loss	0.9900
3:50302051:ACT:A	donor_loss	0.9900
3:50302055:A:AC	donor_gain	0.9900
3:50302056:C:CC	donor_gain	0.9900
3:50300796:GATTC:G	acceptor_gain	0.9800
3:50300797:ATTC:A	acceptor_gain	0.9800
3:50300799:TC:T	acceptor_gain	0.9800
3:50300800:CC:C	acceptor_gain	0.9800
3:50300805:G:C	acceptor_gain	0.9800
3:50300805:G:GC	acceptor_gain	0.9800
3:50301074:CATC:C	acceptor_gain	0.9800
3:50301077:CCTG:C	acceptor_loss	0.9800
3:50301079:T:C	acceptor_loss	0.9800
3:50301145:T:TC	acceptor_gain	0.9800
3:50302056:CCA:C	donor_gain	0.9800
3:50302056:CCAG:C	donor_gain	0.9800

AlphaMissense

2824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50302851:A:G	W36R	0.992
3:50302851:A:T	W36R	0.992
3:50302432:G:C	F175L	0.991
3:50302432:G:T	F175L	0.991
3:50302434:A:G	F175L	0.991
3:50302849:C:A	W36C	0.988
3:50302849:C:G	W36C	0.988
3:50302433:A:C	F175C	0.987
3:50301048:A:C	S310R	0.986
3:50301048:A:T	S310R	0.986
3:50301050:T:G	S310R	0.986
3:50302560:A:G	W133R	0.986
3:50302560:A:T	W133R	0.986
3:50302362:A:G	W199R	0.985
3:50302362:A:T	W199R	0.985
3:50302537:G:C	N140K	0.985
3:50302537:G:T	N140K	0.985
3:50301015:C:A	W321C	0.984
3:50301015:C:G	W321C	0.984
3:50302360:C:A	W199C	0.984
3:50302360:C:G	W199C	0.984
3:50302846:A:C	N37K	0.984
3:50302846:A:T	N37K	0.984
3:50300793:C:G	C333S	0.983
3:50300794:A:T	C333S	0.983
3:50302829:C:G	C43S	0.983
3:50302830:A:T	C43S	0.983
3:50302558:C:A	W133C	0.982
3:50302558:C:G	W133C	0.982
3:50300543:G:C	F416L	0.981

dbSNP variants (sampled 300 via entrez): RS1000278567 (3:50304617 C>G,T), RS1000309822 (3:50304872 G>A), RS1000507779 (3:50313232 G>A), RS1000538894 (3:50313385 C>T), RS1000609497 (3:50303092 G>A,T), RS1000690431 (3:50303393 G>A), RS1001279714 (3:50306152 C>T), RS1001311091 (3:50306552 G>A), RS1001823111 (3:50299658 C>T), RS1002869600 (3:50303051 G>A,C,T), RS1003616600 (3:50307762 A>G), RS1003646004 (3:50308159 C>A), RS1003761596 (3:50301184 G>A), RS1004272453 (3:50304522 G>A,T), RS1004312416 (3:50314379 T>C)

Disease associations

OMIM: gene MIM:607071 | disease phenotypes: MIM:601492

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 9	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 9	Moderate	AR

Mondo (1): mucopolysaccharidosis type 9 (MONDO:0011093)

Orphanet (1): Hyaluronidase deficiency (Orphanet:67041)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000403	Recurrent otitis media
HP:0000934	Chondrocalcinosis
HP:0003170	Abnormal acetabulum morphology
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0004626	Lumbar scoliosis
HP:0005072	Wrist hypermobility
HP:0005280	Depressed nasal bridge
HP:0006094	Finger joint hypermobility
HP:0010485	Hyperextensibility at elbow
HP:0011463	Childhood onset
HP:0020127	Periarticular soft-tissue mass
HP:0030838	Hip pain
HP:0030839	Knee pain
HP:0030840	Ankle pain
HP:0032072	Popliteal synovial cyst
HP:0033640	Acetabular erosions
HP:0100769	Synovitis
HP:6000969	Diminished circulating hyaluronidase activity

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST008843_1	Depressive symptom (appetite changes) (binary trait)	9.000000e-09
GCST008848_2	Depressive symptoms (sum-score)	1.000000e-09
GCST008849_3	Depressive symptoms (binary sum-score)	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563209	Hyaluronidase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4528 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Arsenic Trioxide	increases expression	2
Arsenic	affects methylation, decreases methylation, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
sotorasib	decreases expression, affects cotreatment	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
ferrous chloride	decreases expression	1
4-phenylenediamine	increases expression	1
yessotoxin	increases expression	1
CGP 52608	increases reaction, affects binding	1
entinostat	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression, increases reaction	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
PP242	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	decreases methylation, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1111859	Binding	Inhibition of hyaluronidase	Phenolic constituents of the aerial parts of Cimicifuga simplex and Cimicifuga japonica. — J Nat Prod

Cellosaurus cell lines

1 cell lines: 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_GY29	GM17494	Finite cell line	Female

Clinical trials (associated diseases)

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