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HYAL1
hyaluronidase 1
HYAL1 is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
HYAL1 encodes hyaluronidase 1, a lysosomal enzyme that catalyses the breakdown of hyaluronic acid, a large glycosaminoglycan found throughout connective tissues and the extracellular matrix. The protein plays an essential role in tissue remodelling, cell migration, and the turnover of extracellular matrix components. Pathogenic variants in HYAL1 are inherited in an autosomal recessive pattern, meaning that individuals must inherit altered copies from both parents to develop clinical features. When enzyme activity is severely reduced or absent, hyaluronic acid accumulates in lysosomes, disrupting normal cellular function and leading to multi-system involvement characteristic of lysosomal storage disorders.
What the gene does
Hyaluronidase 1 is a hydrolytic enzyme localised primarily to lysosomes, where it degrades hyaluronic acid into smaller oligosaccharides that can be further processed by other enzymes. Hyaluronic acid is a non-sulphated glycosaminoglycan composed of repeating disaccharide units and serves structural and signalling functions in the extracellular matrix. By cleaving the beta-1,4-glycosidic bonds between N-acetylglucosamine and glucuronic acid residues, HYAL1 facilitates the breakdown of high-molecular-weight hyaluronic acid. This degradation process is essential for normal tissue remodelling, wound healing, and the regulation of cellular processes such as proliferation and migration. The enzyme requires an acidic pH for optimal activity, consistent with the environment within lysosomes. Efficient hyaluronic acid catabolism prevents the pathological accumulation of this substrate in tissues and maintains the balance of extracellular matrix turnover.
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Chromosome location
HYAL1 is located on the short arm of chromosome 3 at position 21.31, designated as 3p21.31. This chromosomal region contains a cluster of related hyaluronidase genes that arose through gene duplication events. The gene structure and regulatory elements contribute to tissue-specific expression patterns, with HYAL1 being expressed in a variety of tissues including liver, kidney, and spleen.
Protein structure
The HYAL1 protein comprises 435 amino acids and includes an EGF-like domain spanning amino acids 354 to 430. This domain typically participates in protein-protein interactions and may contribute to the enzyme's stability or localisation. The catalytic region of the protein contains conserved residues necessary for hyaluronic acid binding and hydrolysis. Post-translational modifications, including glycosylation, are important for proper enzyme folding, stability, and trafficking to lysosomes. The mature enzyme functions optimally in the acidic lysosomal compartment.
Key variants
Pathogenic variants in HYAL1 are rare and typically result in significantly reduced or absent enzyme activity. Most disease-causing variants are loss-of-function changes, including nonsense mutations, frameshift insertions or deletions, and missense variants that disrupt the catalytic site or protein stability. The spectrum of variants reflects the autosomal recessive inheritance pattern, with affected individuals carrying two pathogenic alleles.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.110_134dup | p.Arg46fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.201del | p.Gly68fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.221del | p.Phe74fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.221dup | p.Tyr75fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.390G>A | p.Trp130Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.445C>T | p.Gln149Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.546G>A | p.Trp182Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.663_670dup | p.Gly224fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.81del | p.Asn29fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
c.872_873del | p.Phe290_Tyr291insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of hyaluronoglucosaminidase |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in HYAL1 cause a rare lysosomal storage disorder characterised by the accumulation of hyaluronic acid in tissues. Clinical features may include distinctive facial features, short stature, joint abnormalities, and soft-tissue masses. The severity and specific manifestations can vary depending on the degree of residual enzyme activity. This condition is classified within the broader category of mucopolysaccharidoses, a group of disorders involving glycosaminoglycan metabolism.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HYAL1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
HYAL1 is included on several NHS Genomic Medicine Service gene panels. It appears on the DDG2P panel with a green classification, indicating strong evidence for its role in developmental disorders. The gene is also listed on the Likely inborn error of metabolism panel (green, R98), the Lysosomal storage disorder panel (green, R276), and the Undiagnosed metabolic disorders panel (green). These classifications reflect the established association between HYAL1 variants and lysosomal storage disease, supporting its use in diagnostic genomic testing for individuals with relevant clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the HYAL1 gene do?
HYAL1 encodes an enzyme called hyaluronidase 1 that breaks down hyaluronic acid, a major component of connective tissue. This process is essential for normal tissue remodelling and preventing the build-up of hyaluronic acid in cells.
How are HYAL1 variants inherited?
HYAL1 variants are inherited in an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from both parents to be affected. Carriers, who have one altered copy, typically do not show symptoms.
Is HYAL1 included in NHS genetic testing?
Yes, HYAL1 is included on multiple NHS Genomic Medicine Service panels, including those for lysosomal storage disorders and inborn errors of metabolism, reflecting its established role in rare metabolic disease.