HYAL1 (hyaluronoglucosaminidase 1)

2007-10-01 Demitrios H Vynios Affiliation

Department of Chemistry, University of Patras, 26500 Patras, Greece

Identity

HGNC

HYAL1

LOCATION

3p21.31

IMAGE

LOCUSID

3373

ALIAS

HYAL-1,LUCA1,MPS9,NAT6

DNA/RNA

Description

The HYAL1 gene contains three exons and spans 12,492 bases (start: 50,312,324 bp to end 50,324,816 from 13pter) oriented at the minus strand.

Transcription

Eight alternatively spliced transcript variants of this gene encoding six distinct isoforms have been described. The longest transcript has a length of 2,518 bps, however it is not translated to protein, since, by retaining intron 1 (occurring within exon 1), it has a number of stop codons. The longest transcript that produces active HYAL1 has a length of 2075 bps.

Pseudogene

PHYAL1

Proteins

Note

HYAL1 is a secreted somatic tissue hyaluronidase, and the predominant hyaluronidase in human plasma. Although HYAL1 is predominantly secreted, it has an acid pH optimum in vitro. HYAL1 can degrade high molecular weight hyaluronan to small oligomers, primarily to tetrasaccharides, whereas HYAL2 (the other major human hyaluronidase) high molecular mass hyaluronan to an approximately 20 kDa product (approximatively 50 saccharide units).

Description

Size: 435 amino acids; Molecular mass: 48368 Da. The enzyme belongs to the group of carbohydrate-active enzymes (CASy), termed glycosyl hydrolase 56 family.

Expression

HYAL1 is highly expressed in liver, kidney and heart and weakly expressed in lung, placenta and skeletal muscle. No expression is 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.
HYAL1 expression has been described in squamous cell carcinoma, in small cell lung cancer and glioma lines.

Localisation

It is a secreted enzyme found in plasma and it is also present in lysosomes.

Function

It is a hydrolytic enzyme (endo-beta-acetyl-D-hexosaminidase) with optimum pH about 3.7, acting on hyaluronan, chondroitin and chondroitin sulphate. It possesses also transglycosidase activity using hyaluronan and chondroitin sulphate or chondroitin as substrates. This reaction is not well understood, and the precise enzymatic mechanism is not known.

Homology

The enzyme possesses 70-80 % homology to orthologue hyaluronidases, 40% homology to paralogue hyaluronidases of the human and high homology with HYAL1 of other species.

Mutations

Somatic

There are not extended reports regarding mutations of HYAL1 gene. The patient with hyaluronidase deficiency was a compound heterozygote for two mutations in the HYAL1 gene: a 1412G-A mutation that introduced a nonconservative amino acid substitution (glu268 to lys) in a putative active site residue, and a complex intragenic rearrangement, 1361del37ins14, that resulted in a premature termination codon. In addition, the mutated HYAL1 gene has a markedly different expression pattern than the normal one.

Implicated in

Entity name

Mucopolysaccharidosis type IX (MPS9).

Note

Defects in HYAL1 are the cause of mucopolysaccharidosis type IX, also called hyaluronidase deficiency.

Disease

The clinical features are periarticular soft tissue masses, mild short stature and acetabular erosions, absence of neurological or visceral involvement and high hyaluronan concentration in the serum.

Entity name

Cancer

Note

HYAL1 is inactivated in most lung cancers in a conventional manner, by loss of heterozygosity or by homozygous deletion, at the DNA level. It is also inactivated in many head and neck carcinomas that are tobacco-related by aberrant splicing of the mRNA, so that only the nontranslatable form is transcribed. In addition, the expression of an alternative spliced isoform resulting in active enzyme may negatively regulate bladder tumor growth, infiltration, and angiogenesis. On the other hand, HYAL1 can function as oncogene in many cancers of the prostate and urinary tract and seems to play important role in squamous cell laryngeal carcinoma.

Bibliography

Pubmed ID	Last Year	Title	Authors
17503783	2007	Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis.	Chao KL et al
16713680	2006	Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma.	Christopoulos TA et al
10493834	1999	Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31.	Csóka AB et al
11731267	2001	The six hyaluronidase-like genes in the human and mouse genomes.	Csoka AB et al
9223416	1997	Purification, cloning, and expression of human plasma hyaluronidase.	Frost GI et al
10702795	2000	HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA.	Frost GI et al
16104017	2005	Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysis.	Jedrzejas MJ et al
12684632	2003	Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines.	Junker N et al
9712871	1998	HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.	Lepperdinger G et al
11085536	2000	The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium.	Lerman MI et al
17145867	2006	HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: a negative regulator of bladder cancer.	Lokeshwar VB et al
11929860	2002	Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3.	Shuttleworth TL et al
16522010	2006	Hyaluronidases: their genomics, structures, and mechanisms of action.	Stern R et al
10339581	1999	Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX.	Triggs-Raine B et al

Other Information

Locus ID:

NCBI: 3373
MIM: 607071
HGNC: 5320
Ensembl: ENSG00000114378

Variants:

dbSNP: 3373
ClinVar: 3373
TCGA: ENSG00000114378
COSMIC: HYAL1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000114378	ENST00000266031	Q12794
ENSG00000114378	ENST00000266031	A0A024R2X3
ENSG00000114378	ENST00000320295	Q12794
ENSG00000114378	ENST00000320295	A0A024R2X3
ENSG00000114378	ENST00000395143	Q12794
ENSG00000114378	ENST00000395143	A0A0S2Z3Q0
ENSG00000114378	ENST00000395144	Q12794
ENSG00000114378	ENST00000395144	A0A024R2X3
ENSG00000114378	ENST00000418723	C9JRK1
ENSG00000114378	ENST00000447605	Q12794
ENSG00000114378	ENST00000452672	C9JB49
ENSG00000114378	ENST00000457214	Q12794
ENSG00000114378	ENST00000618175	Q12794
ENSG00000114378	ENST00000618175	A0A024R2X3

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Glycosaminoglycan degradation	KEGG	ko00531
Glycosaminoglycan degradation	KEGG	hsa00531
Lysosome	KEGG	ko04142
Lysosome	KEGG	hsa04142
Metabolic pathways	KEGG	hsa01100
Dermatan sulfate degradation	KEGG	hsa_M00076
Chondroitin sulfate degradation	KEGG	hsa_M00077
Dermatan sulfate degradation	KEGG	M00076
Chondroitin sulfate degradation	KEGG	M00077
Metabolism	REACTOME	R-HSA-1430728
Metabolism of carbohydrates	REACTOME	R-HSA-71387
Glycosaminoglycan metabolism	REACTOME	R-HSA-1630316
Hyaluronan metabolism	REACTOME	R-HSA-2142845
Hyaluronan uptake and degradation	REACTOME	R-HSA-2160916
Chondroitin sulfate/dermatan sulfate metabolism	REACTOME	R-HSA-1793185
CS/DS degradation	REACTOME	R-HSA-2024101

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20960509	2011	Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis.	38
12845686	2003	Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.	37
17503783	2007	Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis.	28
20473947	2011	HYAL1 overexpression is correlated with the malignant behavior of human breast cancer.	27
19345473	2010	HYAL-1 hyaluronidase: a potential prognostic indicator for progression to muscle invasion and recurrence in bladder cancer.	24
17502371	2007	Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis.	23
17415544	2007	Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis.	22
19435493	2009	Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.	20
21829529	2011	Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis.	19
20634891	2010	Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia.	18

Citation

Demitrios H Vynios

HYAL1 (hyaluronoglucosaminidase 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-10-01

Online version: http://atlasgeneticsoncology.org/gene/40903/hyal1