GNPTG
protein-codingN-acetylglucosamine-1-phosphate transferase subunit gamma, the group of MRH domain containing
Gene summary
This gene encodes the gamma sunbunit of the N-acetylglucosamine-1-phosphotransferase complex. This hexameric complex, composed of alpha, beta and gamma subunits, catalyzes the first step in synthesis of a mannose 6-phosphate lysosomal recognition marker. This enzyme complex is necessary for targeting of lysosomal hydrolases to the lysosome. Mutations in the gene encoding the gamma subunit have been associated with mucolipidosis IIIC, also known as mucolipidosis III gamma.[provided by RefSeq, Feb 2010]
- GNPTAG
- C16orf27
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: ClinGen
GNPTG was first reported in relation to GNPTG-mucolipidosis (also known as mucolipidosis type III gamma), an autosomal recessive disorder of lysosomal hydrolase trafficking, in 2000 (Raas-Rothschild et al, PMID: 10712439). GNPTG encodes the gamma subunit of GlcNAc‐1‐phosphotransferase, a hexameric enzyme composed of membrane‐bound alpha‐ and beta‐subunits which are synthesized as a common alpha/beta‐precursor encoded by GNPTAB, in addition to the soluble gamma subunit encoded by GNPTG. GlcNAc-1-phosphotransferase catalyzes the first step of the formation of mannose 6-phosphate (M6P) on specific soluble lysosomal hydrolases. M6P is essential for the trafficking of these lysosomal enzymes from the trans-Golgi network to the lysosomes via M6P receptors. Without M6P, newly synthesized lysosomal enzymes are missorted into the extracellular space and are unable to breakdown specific substrates in lysosomes (for reviews, see Velho et al, 2019, PMID: 30882951; and Khan and Tomatsu, 2020, PMID: 32957425). As a result, various macromolecules accumulate in the lysosomes in different tissues causing the characteristic symptoms of mucolipidosis. Biallelic variants in GNPTG are reported in individuals with mucolipiosis type III gamma. This condition is characterized by gradual mild coarsening of facial features, spinal deformities including scoliosis and hyperlordosis, genu valgum, restricted joint mobility, short stature, and characteristic radiographic findings. Most patients have normal intellectual capacity, and organomegaly is not present. Mucolipidosis type II gamma is typically milder and less rapidly progressive than mucolipidosis type II, which is caused by variants in GNPTAB (Raas-Rothschild & Spiegel, 2019, PMID: 20301784). About 50 different GNPTG variants have been identified in individuals with mucolipiosis type III gamma, about 80% of which result in formation of a premature stop codon (Velho et al, 2019, PMID: 30882951). The mechanism of pathogenicity is loss of function. Seventeen variants (including nonsense, frameshift, splice site, missense, in-frame deletion) reported in 12 probands in 4 publications (Raas-Rothschild et al, 2000, PMID: 10712439; Raas-Rothschild et al, 2004, PMID: 15060128; Persichetti et al, 2009, PMID: 19370764; Velho et al, 2014, PMID: 27896079) are included in this curation in addition to segregation data from a large, consanguineous family (Raas-Rothschild et al, 2000, PMID: 10712439). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by the biochemical function of the gene product, which is consistent with the biochemical and clinical features of mucolipidosis type III gamma (Lee et al, 2007, PMID: 17652091; Di Lorenzo et al, 2018, PMID: 29773673), rescue in patient cells (Zarghooni et al, 2009, PMID: 19938078), and the features reported in Gnptg knock out mouse and zebrafish models (Vogel et al, 2009, PMID: 19261645; Idol et al, 2014, PMID: 25314316; Flannagan-Steet et al, 2016, PMID: 27241848). In summary, GNPTG is definitively associated with autosomal recessive GNPTG-mucolipidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP (SOP v9) on December 28, 2022.
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009652
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Musculoskeletal
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
Comments: The condition may include severe cardiac manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GNPTG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032520.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 248 | 253 | |||
| missense | 3 | 225 | 19 | 247 | ||
| nonsense | 18 | 17 | 4 | 1 | 40 | |
| start loss | 3 | 4 | 7 | |||
| frameshift | 49 | 35 | 18 | 1 | 103 | |
| splice donor/acceptor (+/-2bp) | 12 | 37 | 3 | 52 | ||
| Total | 79 | 95 | 259 | 269 | 0 | 702 |
Highest pathogenic variant AF is 0.00016483142
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115909.1 | 11 | MANE Select | |
| Ensembl | ENSP00000204679.4 | 11 | MANE Select | |
| Ensembl | ENSP00000434413.1 | 4 | Standard | |
| Ensembl | ENSP00000480060.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gnptg | Danio rerio | Structure: whole organism Quality: decreased life span abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
Biological Process
- N-glycan processing to lysosome
- carbohydrate phosphorylation
Molecular Function
- UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase activity
- protein homodimerization activity
Cellular Component
- Golgi membrane
- Golgi apparatus
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000204679
- Coding exons
- 11
- Length
- 11429
- Individuals with no LoFs
- 125651
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 97
- Defined
- 125748
- p
- 0.000386
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.06 | 253 | 176 | 1.44 | 0.0000120 | 1960 |
| Missense (PolyPhen) | 64 | 49.319 | 1.2977 | 581 | ||
| Synonymous | -4.86 | 132 | 77.6 | 1.70 | 0.00000586 | 582 |
| Loss of Function | 0.853 | 15 | 19.0 | 0.789 | 0.00000102 | 210 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00068 | 0.00068 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00089 | 0.00089 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00045 | 0.00045 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-catalytic subunit of the N-acetylglucosamine-1- phosphotransferase complex, an enzyme that catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. Binds and presents the high mannose glycans of the acceptor to the catalytic alpha and beta subunits (GNPTAB). Enhances the rate of N-acetylglucosamine- 1-phosphate transfer to the oligosaccharides of acid hydrolase acceptors. {ECO:0000269|PubMed:10712439, ECO:0000269|PubMed:19955174}.;
- Disease
- DISEASE: Mucolipidosis type III complementation group C (MLIIIC) [MIM:252605]: Autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (GlcNAc- phosphotransferase) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Typical clinical findings include stiffness of the hands and shoulders, claw-hand deformity, scoliosis, short stature, coarse facies, and mild mental retardation. Radiographically, severe dysostosis multiplex of the hip is characteristic and frequently disabling. The clinical diagnosis can be confirmed by finding elevated serum lysosomal enzyme levels and/or decreased lysosomal enzyme levels in cultured fibroblasts. {ECO:0000269|PubMed:10712439, ECO:0000269|PubMed:15060128, ECO:0000269|PubMed:15532026, ECO:0000269|PubMed:19370764, ECO:0000269|PubMed:24316125, ECO:0000269|PubMed:26108976, ECO:0000269|PubMed:27038293}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in GNPTG have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech. {ECO:0000269|PubMed:20147709}.;
Recessive Scores
- pRec
- 0.144
Intolerance Scores
- LoFtool
- 0.331
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.819
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |