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NAGLU
N-acetyl-alpha-glucosaminidase
The NAGLU gene provides instructions for an enzyme essential for breaking down complex sugar molecules within cellular compartments called lysosomes, and pathogenic variants are associated with Mucopolysaccharidosis type III (Sanfilippo syndrome). The NAGLU gene is responsible for producing the alpha-N-acetylglucosaminidase enzyme, which plays a critical role in cellular waste recycling.
NAGLU is located on the long (q) arm of chromosome 17, at band 17q21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The NAGLU gene, or N-acetyl-alpha-glucosaminidase, is a key component in the body's cellular recycling system. It encodes an enzyme that functions within lysosomes, which are organelles responsible for breaking down and recycling various molecules. This gene's proper function is vital for maintaining cellular health and preventing the harmful build-up of certain substances within cells.
What the gene does
The NAGLU gene provides the blueprint for an enzyme named alpha-N-acetylglucosaminidase. This enzyme is primarily active within lysosomes, cellular compartments that act as the cell's digestive and waste disposal units. Its specific role is in the step-wise breakdown of large molecules known as glycosaminoglycans (GAGs). GAGs are complex sugar molecules that resemble long strings, and to process them, individual sugar units must be removed sequentially. The alpha-N-acetylglucosaminidase enzyme is responsible for cleaving a specific sugar, N-acetylglucosamine, when it is located at the end of a GAG chain. When this enzyme's activity is impaired, the breakdown of these GAGs is disrupted, leading to their accumulation within cells.
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Chromosome location
The NAGLU gene is located on chromosome 17, specifically at position 17q21.2. This genomic location indicates its precise address within the human genome, helping to identify its position relative to other genes and genetic markers on chromosome 17.
Protein structure
The NAGLU gene codes for a protein that is 743 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the NAGLU gene can lead to a reduction or complete loss of function of the alpha-N-acetylglucosaminidase enzyme. These genetic changes can range from single DNA building block alterations to more complex mutations, all impacting the enzyme's ability to effectively break down glycosaminoglycans.
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.1022-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2V |
c.1238del | p.Asn413fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.1348C>T | p.Gln450Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.1482G>A | p.Trp494Ter | Pathogenic/Likely pathogenic | ★★☆☆ | NAGLU-related disorder |
c.1649T>C | p.Leu550Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.1675G>T | p.Asp559Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.2080C>T | p.Gln694Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.2099del | p.Asn700fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.457G>T | p.Glu153Ter | Pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-B |
c.531+1G>C | - | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2V |
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 NAGLU gene are the underlying cause of Mucopolysaccharidosis type III, specifically type IIIB (MPS IIIB), also known as Sanfilippo syndrome. This condition is inherited in an autosomal recessive manner. The deficiency of the alpha-N-acetylglucosaminidase enzyme leads to the accumulation of certain glycosaminoglycans, primarily heparan sulphate, which has significant effects on neurological development and function.
Inheritance pattern
Conditions caused by pathogenic NAGLU 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 NAGLU gene is recognised within the NHS Genomic Medicine Service's PanelApp, indicating its clinical relevance in the UK. It is part of several 'green' panels, meaning there is strong evidence for its association with specific conditions. These panels include DDG2P, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Mucopolysaccharideosis, Gaucher, Fabry, Mucopolysaccharidosis type IIIB (R292), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the NAGLU gene?
The NAGLU gene provides instructions for creating the alpha-N-acetylglucosaminidase enzyme, which is crucial for breaking down specific complex sugar molecules called glycosaminoglycans within cellular lysosomes.
What condition is associated with variants in the NAGLU gene?
Variants in the NAGLU gene are primarily associated with Mucopolysaccharidosis type III (MPS III), specifically type IIIB, also known as Sanfilippo syndrome.
How is Mucopolysaccharidosis type III inherited?
Mucopolysaccharidosis type III, including type IIIB caused by NAGLU variants, is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
References
- Ohmi K, Kudo LC, Ryazantsev S. Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proceedings of the National Academy of Sciences of the United States of America. 2009. PMID: 19416848
- Valstar MJ, Ruijter GJ, van Diggelen OP. Sanfilippo syndrome: a mini-review. Journal of inherited metabolic disease. 2008. PMID: 18392742
- Ficko-Blean E, Stubbs KA, Nemirovsky O. Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB. Proceedings of the National Academy of Sciences of the United States of America. 2008. PMID: 18443291
- Beesley CE, Jackson M, Young EP. Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB). Journal of inherited metabolic disease. 2005. PMID: 16151907