OGT
protein-codingO-linked N-acetylglucosamine (GlcNAc) transferase, the group of NSL histone acetyltransferase complex|O-linked N-acetylglucosaminyltransferases|Tetratricopeptide repeat domain containing
Gene summary
This gene encodes a glycosyltransferase that catalyzes the addition of a single N-acetylglucosamine in O-glycosidic linkage to serine or threonine residues. Since both phosphorylation and glycosylation compete for similar serine or threonine residues, the two processes may compete for sites, or they may alter the substrate specificity of nearby sites by steric or electrostatic effects. The protein contains multiple tetratricopeptide repeats that are required for optimal recognition of substrates. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~42.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0030907
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0030907
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0030907
Submitter: ClinGen
The OGT gene (OMIM_300255) is located on chromosome Xq13.1 and encodes the O-linked N-acetyleglucosamine (O-GlCNAc) transferase, which is an enzyme that modifies intracellular proteins post-translationally by transferring N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to serine and threonine residues of protein substrates through O-glycosylation. OGT was first reported in relation to intellectual disability, X-linked 106 (MONDO:0030907) in 2017 (Willems et al., 2017, PMID 28584052; Vaidyanathan et al., 2017, PMID 28302723). Ten variants (9 missense, 1 splice region variant) that have been reported in 10 probands in 10 publications (PMIDs:32080367, 28584052, 28302723, 31627256, 31296563, 29769320, 29606577, 37334838, 35970915, 33349918) are included in this curation. These affected individuals have been described with de novo or maternally inherited missense variants presenting with developmental delay, intellectual disability, dysmorphic features of the face and hands, eye abnormalities and hypotonia. Although the exact mechanism of how missense variants in OGT results in a syndromic intellectual disability disorder is unknown, each described variant has a collection of function evidence demonstrating detrimental effects of these missense variants on OGT activity. Additional evidence supporting this gene-disease relationship includes a conditional mouse model, transcriptome analysis on mutant hESC, and protein interaction between OGT and genes linked to syndromes with overlapping features (e.g., Sin3A and HCFC1) (PMIDs:29769320, 32896380, 12150998, 21295698). In summary, the available evidence of this gene-disease relationship is convincing due to the essential role OGT plays in development, the high missense constraint of variation in OGT, and the functional evaluation of variants and phenotypic similarities across the affected individuals described in the literature. Currently there is moderate evidence to support the relationship between OGT and X-linked syndromic intellectual disability. The gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on February 3, 2021 and was re-evaluated on August 8, 2024. As a result of this re-evaluation, although there were new published case reports included (3 missense variants from PMIDs: 35970915, 33349918, 37334838) and new experimental evidence in the form of biochemical evidence (PMID: 26237509), a mouse model (PMID: 38566589) and a drosophila model (PMID: 35500025), the classification did not change. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date of August 8, 2024 (SOP Version 10).
Inheritance Pattern: XL
Disease ID:MONDO:0030907
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0030907
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to OGT variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181672.3. 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 | 24 | 27 | 8 | 59 | ||
| missense | 5 | 11 | 236 | 2 | 254 | |
| nonsense | 9 | 9 | ||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 27 | 27 | ||||
| Total | 6 | 11 | 297 | 29 | 8 | 351 |
Highest pathogenic variant AF is 0.0000016627508
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_858058.1 | 22 | MANE Select | |
| Ensembl | ENSP00000362824.3 | 22 | MANE Select | |
| RefSeq | NP_858059.1 | 22 | Standard | |
| Ensembl | ENSP00000362805.3 | 22 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ogt.2 | Danio rerio | Structure: head Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Insulin resistance - Homo sapiens (human)
- Other types of O-glycan biosynthesis - Homo sapiens (human)
- Ectoderm Differentiation
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- regulation of glycolytic process
- regulation of gluconeogenesis
- regulation of transcription by RNA polymerase II
- protein O-linked glycosylation
- apoptotic process
Molecular Function
- protein binding
- phosphatidylinositol-3,4,5-trisphosphate binding
- acetylglucosaminyltransferase activity
- protein N-acetylglucosaminyltransferase activity
- histone acetyltransferase activity (H4-K5 specific)
Cellular Component
- histone acetyltransferase complex
- nucleus
- nucleoplasm
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373719
- Coding exons
- 22
- Length
- 42815
- Individuals with no LoFs
- 102448
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 102449
- p
- 0.00000488
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.67 | 82 | 402 | 0.204 | 0.0000309 | 6930 |
| Missense (PolyPhen) | 12 | 152.98 | 0.078443 | 2558 | ||
| Synonymous | 1.30 | 121 | 141 | 0.861 | 0.0000107 | 2007 |
| Loss of Function | 5.64 | 0 | 37.0 | 0.00 | 0.00000299 | 619 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000015 | 0.000011 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear proteins resulting in their modification with a beta- linked N-acetylglucosamine (O-GlcNAc) (PubMed:26678539, PubMed:23103939, PubMed:21240259, PubMed:21285374, PubMed:15361863). Glycosylates a large and diverse number of proteins including histone H2B, AKT1, EZH2, PFKL, KMT2E/MLL5, MAPT/TAU and HCFC1. Can regulate their cellular processes via cross-talk between glycosylation and phosphorylation or by affecting proteolytic processing (PubMed:21285374). Probably by glycosylating KMT2E/MLL5, stabilizes KMT2E/MLL5 by preventing its ubiquitination (PubMed:26678539). Involved in insulin resistance in muscle and adipocyte cells via glycosylating insulin signaling components and inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1 phosphorylation and attenuating insulin signaling (By similarity). Involved in glycolysis regulation by mediating glycosylation of 6-phosphofructokinase PFKL, inhibiting its activity (PubMed:22923583). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Plays a key role in chromatin structure by mediating O-GlcNAcylation of 'Ser-112' of histone H2B: recruited to CpG-rich transcription start sites of active genes via its interaction with TET proteins (TET1, TET2 or TET3) (PubMed:22121020, PubMed:23353889). As part of the NSL complex indirectly involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). O-GlcNAcylation of 'Ser-75' of EZH2 increases its stability, and facilitating the formation of H3K27me3 by the PRC2/EED-EZH2 complex (PubMed:24474760). Regulates circadian oscillation of the clock genes and glucose homeostasis in the liver. Stabilizes clock proteins ARNTL/BMAL1 and CLOCK through O-glycosylation, which prevents their ubiquitination and subsequent degradation. Promotes the CLOCK-ARNTL/BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2 and CRY1/2 (PubMed:12150998, PubMed:19451179, PubMed:20018868, PubMed:20200153, PubMed:21285374, PubMed:15361863). O-glycosylates HCFC1 and regulates its proteolytic processing and transcriptional activity (PubMed:21285374, PubMed:28584052, PubMed:28302723). Regulates mitochondrial motility in neurons by mediating glycosylation of TRAK1 (By similarity). Glycosylates HOXA1 (By similarity). {ECO:0000250|UniProtKB:P56558, ECO:0000250|UniProtKB:Q8CGY8, ECO:0000269|PubMed:12150998, ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:19451179, ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:20018868, ECO:0000269|PubMed:20200153, ECO:0000269|PubMed:21240259, ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:22121020, ECO:0000269|PubMed:22923583, ECO:0000269|PubMed:23103939, ECO:0000269|PubMed:23353889, ECO:0000269|PubMed:24474760, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:28302723, ECO:0000269|PubMed:28584052}.;
- Disease
- DISEASE: Note=Regulation of OGT activity and altered O- GlcNAcylations are implicated in diabetes and Alzheimer disease. O-GlcNAcylation of AKT1 affects insulin signaling and, possibly diabetes. Reduced O-GlcNAcylations and resulting increased phosphorylations of MAPT/TAU are observed in Alzheimer disease (AD) brain cerebrum.; DISEASE: Mental retardation, X-linked 106 (MRX106) [MIM:300997]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:26273451, ECO:0000269|PubMed:28302723, ECO:0000269|PubMed:28584052}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.326
Intolerance Scores
- RVIS EVS
- -0.41
- RVIS percentile EVS
- 26.23
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.853
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |