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NEU1
neuraminidase 1
The NEU1 gene encodes neuraminidase 1, a lysosomal enzyme vital for breaking down specific sugar molecules, with mutations linked to the rare inherited disorder sialidosis. The NEU1 gene provides instructions for producing the neuraminidase 1 enzyme, which plays a critical role within cellular lysosomes.
NEU1 is located on the short (p) arm of chromosome 6, at band 6p21.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The NEU1 gene, or neuraminidase 1, is crucial for normal cellular function, particularly within lysosomes. These cellular compartments act as recycling centres, utilising enzymes to break down and process various biological materials. NEU1 encodes an enzyme that specifically targets and removes sialic acid from larger sugar molecules (oligosaccharides) attached to proteins, a process essential for proper cellular waste management.
Disruptions to the NEU1 gene's function can lead to an inability to properly break down these molecules, resulting in their harmful accumulation within cells, which underlies conditions like sialidosis.
What the gene does
The neuraminidase 1 enzyme, encoded by the NEU1 gene, is located in the lysosomes, which are organelles responsible for cellular degradation and recycling. Its primary function involves hydrolysing terminal sialic acid residues from oligosaccharides, glycoproteins, and glycolipids. This enzymatic activity is crucial for the breakdown of complex sugar molecules, preventing their accumulation within the lysosomes.
The NEU1 enzyme works by cleaving specific chemical bonds, facilitating the catabolism of these large molecules. The proper functioning of this enzyme is integral to maintaining cellular health and preventing the build-up of metabolic by-products that can become toxic if not processed effectively.
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Chromosome location
The NEU1 gene is situated on chromosome 6, specifically at position 6p21.33. This chromosomal location indicates where the gene can be found within the human genome, providing a reference point for genetic studies and understanding its inheritance patterns.
Protein structure
The neuraminidase 1 protein consists of 415 amino acids and features several distinct functional regions. It contains a FRIP motif located at amino acids 77-80, which is involved in protein-protein interactions. An active site loop, crucial for the enzyme's catalytic activity and requiring activation by CTSA, spans amino acids 93-112. The protein also includes four BNR repeats: BNR 1 at 112-123, BNR 2 at 172-183, BNR 3 at 231-242, and BNR 4 at 347-358. Finally, an internalization signal located at amino acids 412-415 plays a role in directing the protein to its correct cellular location.
Key variants
Genetic variations within the NEU1 gene can lead to alterations in the neuraminidase 1 enzyme. These changes can range from single amino acid substitutions to larger deletions, affecting the enzyme's structure, stability, or its ability to perform its function. Many identified variants result in a deficiency of the NEU1 enzyme, impacting its critical role in breaking down complex sugar 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.1004C>A | p.Pro335Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis |
c.1021C>T | p.Arg341Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis type 2 |
c.1109A>G | p.Tyr370Cys | Pathogenic | ★★☆☆ | Lysosomal storage disease |
c.160G>A | p.Val54Met | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis |
c.163C>T | p.Gln55Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis |
c.3G>A | p.Met1Ile | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.692T>A | p.Leu231His | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis |
c.880C>T | p.Arg294Cys | Pathogenic/Likely pathogenic | ★★☆☆ | NEU1-related disorders |
c.913C>T | p.Arg305Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Sialidosis type 2 |
c.982G>A | p.Gly328Ser | Pathogenic | ★★☆☆ | Sialidosis |
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 NEU1 gene are primarily associated with sialidosis, an inherited lysosomal storage disorder. In sialidosis, a deficiency of the neuraminidase 1 enzyme causes the accumulation of undigested sugar molecules, specifically sialic acid-containing oligosaccharides, within the lysosomes of various cells throughout the body. This build-up leads to a range of symptoms affecting multiple organ systems.
- Sialidosis Dedicated page coming soon
UK clinical status
The NEU1 gene is included in several expert-curated panels within the UK's NHS Genomic Medicine Service via PanelApp. It is green-rated for conditions such as "Ataxia and cerebellar anomalies - childhood onset", "Foetal anomalies (R21)", "Foetal hydrops", "Hereditary ataxia, adult onset", "Intellectual disability", "Likely inborn error of metabolism (R98)", "Lysosomal storage disorder (R276)", "Mucopolysaccharideosis, Gaucher, Fabry", "Skeletal dysplasia (R104)", and "Undiagnosed metabolic disorders". This indicates that there is strong evidence supporting a gene-disease association for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the NEU1 gene?
The NEU1 gene provides instructions for the neuraminidase 1 enzyme, which breaks down large sugar molecules by removing sialic acid within cellular lysosomes. This process is essential for proper cellular waste management.
What happens if the NEU1 gene doesn't function correctly?
If the NEU1 gene does not function correctly, the neuraminidase 1 enzyme becomes deficient, leading to the accumulation of undigested sugar molecules in lysosomes. This can cause conditions like sialidosis, affecting various bodily systems.
Is NEU1 associated with any specific genetic conditions?
Yes, pathogenic variants in the NEU1 gene are primarily associated with sialidosis, which is a rare inherited lysosomal storage disorder characterised by the build-up of specific sugar molecules in cells.
References
- Wu X, Steigelman KA, Bonten E. Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice. Biochimica et biophysica acta. 2010. PMID: 19857571
- Zanoteli E, van de Vlekkert D, Bonten EJ. Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue. Biochimica et biophysica acta. 2010. PMID: 20388541
- Caciotti A, Di Rocco M, Filocamo M. Type II sialidosis: review of the clinical spectrum and identification of a new splicing defect with chitotriosidase assessment in two patients. Journal of neurology. 2009. PMID: 19568825
- Yogalingam G, Bonten EJ, van de Vlekkert D. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Developmental cell. 2008. PMID: 18606142
- Pattison S, Pankarican M, Rupar CA. Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression. Human mutation. 2004. PMID: 14695530
- Seyrantepe V, Poupetova H, Froissart R. Molecular pathology of NEU1 gene in sialidosis. Human mutation. 2003. PMID: 14517945