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GALNS
galactosamine (N-acetyl)-6-sulfatase
The GALNS gene provides instructions for an enzyme called N-acetylgalactosamine 6-sulfatase, which plays a crucial role in breaking down specific large sugar molecules within cells. The GALNS gene is responsible for producing the N-acetylgalactosamine 6-sulfatase enzyme, vital for cellular waste processing.
GALNS is located on the long (q) arm of chromosome 16, at band 16q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The GALNS gene encodes for the enzyme N-acetylgalactosamine 6-sulfatase, a lysosomal hydrolase. This enzyme is primarily involved in the degradation pathways of glycosaminoglycans (GAGs), complex sugar molecules that are components of connective tissues. Proper functioning of this enzyme is essential for cellular metabolism and the prevention of GAG accumulation within lysosomes, cellular compartments responsible for waste breakdown.
Disruptions in the GALNS gene can impair the enzyme's function, leading to the build-up of specific GAGs, notably keratan sulphate. This accumulation is characteristic of lysosomal storage disorders, affecting various bodily systems.
What the gene does
The N-acetylgalactosamine 6-sulfatase enzyme, encoded by the GALNS gene, is located within cellular lysosomes. Its primary function is to break down specific types of large sugar molecules known as glycosaminoglycans (GAGs), or mucopolysaccharides. More precisely, this enzyme facilitates the removal of a sulphate chemical group from keratan sulphate, a GAG particularly abundant in cartilage and the cornea of the eye. This enzymatic activity is a critical step in the recycling process of these complex molecules, preventing their harmful accumulation. When the enzyme's function is reduced or eliminated, keratan sulphate cannot be properly degraded, leading to its build-up within cells and tissues throughout the body.
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Chromosome location
The GALNS gene is situated on chromosome 16 at position 16q24.3. It is inherited in an autosomal recessive (AR) pattern, meaning an individual must inherit two affected copies of the gene (one from each parent) to develop a condition associated with GALNS variants.
Protein structure
The N-acetylgalactosamine 6-sulfatase protein consists of 522 amino acids. It features a critical Catalytic domain, spanning amino acids 27 to 379, which is essential for the enzyme's sulphate-removing activity on glycosaminoglycan substrates. The overall structure is crucial for its correct folding and lysosomal targeting.
Key variants
Variants within the GALNS gene can alter the production or function of the N-acetylgalactosamine 6-sulfatase enzyme. These genetic changes can range from single DNA building block alterations to larger deletions or insertions. Such variants typically lead to a reduction or complete loss of enzyme activity, preventing the proper breakdown of specific cellular molecules.
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.1242+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.1298_1299insCTTTTCC | p.Glu433fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.1318_1319del | p.Leu440fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.1339G>A | p.Asp447Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Morquio syndrome |
c.423-11_425del | - | Pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.454del | p.Pro151_Leu152insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.552G>A | p.Trp184Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.675dup | p.Phe226fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.714del | p.Val239fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
c.758+1G>A | - | Pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-IV-A |
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
Pathogenic variants in the GALNS gene are known to cause Mucopolysaccharidosis type IVA (Morquio A). This condition is characterised by the accumulation of keratan sulphate due to insufficient enzyme activity. This leads to a range of symptoms primarily affecting skeletal development, vision, and other connective tissues.
Inheritance pattern
Conditions caused by pathogenic GALNS 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
The GALNS gene is included on several NHS England Genomic Medicine Service national test panels. These include panels for conditions such as Foetal anomalies (R21), Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), Lysosomal storage disorder (R276), and Mucopolysaccharidosis type IVA (R287), indicating its recognised clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the GALNS gene?
The GALNS gene provides instructions for an enzyme called N-acetylgalactosamine 6-sulfatase, which is responsible for breaking down large sugar molecules, specifically keratan sulphate, within the cell's lysosomes.
Which condition is primarily associated with variants in the GALNS gene?
Variants in the GALNS gene are primarily associated with Mucopolysaccharidosis type IVA, also known as Morquio A syndrome. This condition results from the accumulation of keratan sulphate due to enzyme deficiency.
How is Mucopolysaccharidosis type IVA inherited?
Mucopolysaccharidosis type IVA is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered GALNS gene, one from each parent, to develop the condition.
References
- Montaño AM, Sukegawa K, Kato Z. Effect of 'attenuated' mutations in mucopolysaccharidosis IVA on molecular phenotypes of N-acetylgalactosamine-6-sulfate sulfatase. Journal of inherited metabolic disease. 2007. PMID: 17876718
- Tomatsu S, Montaño AM, Lopez P. Determinant factors of spectrum of missense variants in mucopolysaccharidosis IVA gene. Molecular genetics and metabolism. 2006. PMID: 16837223
- Tomatsu S, Montaño AM, Nishioka T. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Human mutation. 2005. PMID: 16287098