GeneBe

NEU1

protein-coding

neuraminidase 1, the group of Neuraminidases

Gene summary

The protein encoded by this gene is a lysosomal enzyme that cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter is also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis, a lysosomal storage disease that can be type 1 (cherry red spot-myoclonus syndrome or normosomatic type), which is late-onset, or type 2 (the dysmorphic type), which occurs at an earlier age with increased severity. [provided by RefSeq, Jul 2008]

Previous symbols:
  • NEU

MANE transcript

NM_000434.4

Inheritance

AR

ClinVar variants

P:72U:90B:134

Top phenotype

Neuraminidase deficiency

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr6:31,857,063-31,862,905

External References & Databases

Ensembl (ENSG00000204386)NCBI Gene (4758)OMIM (608272)HGNC:7758GenCCUniProt (Q99519)AlphaFoldClinVar (NEU1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sialidosis type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009738

Submitter: G2P

sialidosis type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009738

Submitter: Natera

sialidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017734

Submitter: ClinGen

The relationship between the NEU1 gene and sialidosis, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 1, 2022. NEU1 encodes neuraminidase 1 (PMID: 8985184), an enzyme that is involved in degradation of sialated glyconguates via hydrolyzing terminal N-acetylated neuraminic acids (sialic acids) in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates (as reviewed in PMID: 26949572). Patients with sialidosis show deficient neuraminidase I activity (PMID: 836321, PMID: 610423), leading to accumulation of sialylated oligosaccharides and glycoproteins and urinary excretion of sialylated oligosaccharides and glycoproteins and resulting in characteristic clinical disease manifestations including skeletal anomalies, coarse facies, hepatosplenomegaly, and neurologic impairment (as reviewed in PMID: 26949572). The disease mechanism of sialidosis is loss of function. Sialidosis was first reported in 1968 by Spranger et al. (PMID: 4235073) and the first report of biallelic variants in NEU1 among sialidosis cases was in 1996 by Bonten et al. (PMID: 8985184). Both case-level (genetic) and experimental evidence support the relationship between NEU1 and sialidosis. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 8985184, PMID: 10767332, PMID: 9054950, PMID: 11702224, PMID: 11470272, PMID: 14695530, PMID: 18343720). In total, fourteen variants from ten probands in seven publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between NEU1 and sialidosis includes: the biochemical function of the gene product (neuraminidase 1) being consistent with the clinical and biochemical findings identified individuals with sialidosis (PMID: 8985184, PMID: 836321, PMID: 610423, PMID: 26949572); the biochemical and clinical features of NEU1 knockout mice (PMID: 12023988); and rescue of enzyme function via chaperone-mediated gene therapy in NEU1 transgenic mice (PMID: 23770387). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, NEU1 is definitively associated with sialidosis. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9). **Data provided by the ClinGen Prenatal GCEP on January 28, 2025:** Features of sialidosis that can be identified prenatally by fetal imaging include hydrops, ascites, pleural effusion, cardiomegaly, pericardial effusion, and hepatosplenomegaly (PMID: 11063730, 1119501). Neonates may also have hypotonia, dysostosis multiplex, and coarse facial features (PMID: 23433491, 25223955). Stillbirth or early death in individuals with congenital sialidosis is common (PMID: 11063730, 11195014). Note: This addition of the data from the ClinGen Prenatal GCEP does not change the scoring or classification of the gene-disease relationship that was approved by the ClinGen Lysosomal Diseases GCEP.

sialidosis type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009738

Submitter: PanelApp Australia

sialidosis type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009738

Submitter: Labcorp Genetics (formerly Invitae)

congenital sialidosis type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019682

Submitter: Orphanet

sialidosis type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019346

Submitter: Orphanet

juvenile sialidosis type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019681

Submitter: Orphanet

sialidosis type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009738

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Neuraminidase deficiencyAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic ; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 610425; 610423; 107795; 6777097; 6839532; 3742847; 8985184; 9054950; 11063730; 11829139; 14695530; 15908988; 19568825Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEU1 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 272
Inborn genetic diseasesTotal: 52
Sialidosis type 2Total: 52
not specifiedTotal: 21
NEU1-related disorderTotal: 16
SialidosisTotal: 16
NEU1-related disordersTotal: 6
Sialidosis type 1Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000434.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
110
clinvar
 112
missense
9
clinvar
23
clinvar
87
clinvar
23
clinvar
1
clinvar
 143
nonsense
12
clinvar
2
clinvar
1
clinvar
 15
start loss
1
clinvar
 1
frameshift
13
clinvar
3
clinvar
 16
splice donor/acceptor (+/-2bp)
4
clinvar
4
clinvar
1
clinvar
 9
Total3834901331296

Highest pathogenic variant AF is 0.00003593543

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000434.4RefSeqNP_000425.16MANE Select
ENST00000375631.5EnsemblENSP00000364782.46MANE Select
ENST00000491768.5EnsemblENSP00000433127.15Standard
ENST00000850553.1EnsemblENSP00000520846.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Other glycan degradation - Homo sapiens (human)
  • Sphingolipid metabolism - Homo sapiens (human)
  • Neutrophil degranulation
  • Metabolism of lipids

Biological Process

  • glycosphingolipid metabolic process
  • ganglioside catabolic process
  • oligosaccharide catabolic process
  • neutrophil degranulation

Molecular Function

  • exo-alpha-sialidase activity
  • protein binding
  • alpha-sialidase activity
  • exo-alpha-(2->3)-sialidase activity
  • exo-alpha-(2->6)-sialidase activity

Cellular Component

  • extracellular region
  • cytoplasm
  • lysosome
  • lysosomal membrane
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000375631
Coding exons
6
Length
5248
Individuals with no LoFs
125713
Homozygous LoFs
0
Heterozygous LoFs
23
Defined
125736
p
0.0000915
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.421872500.7470.00001602677
Missense (PolyPhen)71103.670.684851122
Synonymous1.52871070.8130.00000690886
Loss of Function2.111020.20.4940.00000135178

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000660.000062rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.0000910.000088rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the removal of sialic acid (N-acetylneuraminic acid) moities from glycoproteins and glycolipids. To be active, it is strictly dependent on its presence in the multienzyme complex. Appears to have a preference for alpha 2-3 and alpha 2-6 sialyl linkage. {ECO:0000269|PubMed:25153125, ECO:0000269|PubMed:8985184}.;
Disease
DISEASE: Sialidosis (SIALIDOSIS) [MIM:256550]: Lysosomal storage disease occurring as two types with various manifestations. Type 1 sialidosis (cherry red spot-myoclonus syndrome or normosomatic type) is late-onset and it is characterized by the formation of cherry red macular spots in childhood, progressive debilitating myoclonus, insiduous visual loss and rarely ataxia. The diagnosis can be confirmed by the screening of the urine for sialyloligosaccharides. Type 2 sialidosis (also known as dysmorphic type) occurs as several variants of increasing severity with earlier age of onset. It is characterized by the presence of abnormal somatic features including coarse facies and dysostosis multiplex, vertebral deformities, mental retardation, cherry-red spot/myoclonus, sialuria, cytoplasmic vacuolation of peripheral lymphocytes, bone marrow cells and conjunctival epithelial cells. {ECO:0000269|PubMed:10767332, ECO:0000269|PubMed:10944856, ECO:0000269|PubMed:11063730, ECO:0000269|PubMed:11279074, ECO:0000269|PubMed:11829139, ECO:0000269|PubMed:14695530, ECO:0000269|PubMed:25153125, ECO:0000269|PubMed:8985184, ECO:0000269|PubMed:9054950}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.303
RVIS EVS
-0.23
RVIS percentile EVS
37.11

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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