GMPPB
protein-codingGDP-mannose pyrophosphorylase B
Gene summary
This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0700084
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018277
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018278
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700084
Submitter: ClinGen
*GMPPB* was first reported in relation to autosomal recessive myopathy caused by variation in *GMPPB* (muscular dystrophy-dystroglycanopathy included) in 2013, characterizing several patients with a highly variable phenotype (Carss et al., PMID: 23768512). The most severely affected patient had severe developmental delays, retinal dysfunction, and cerebellar hypoplasia reminiscent of muscle-eye-brain disease. Four patients presented with a milder phenotype with intellectual disability and variable cerebellar hypoplasia, and three patients had no developmental phenotypes and a pattern of muscle weakness/dystrophy consistent with limb-girdle muscular dystrophy. All patients showed reduced glycosylation of alpha-dystroglycan, suggesting a dystroglycanopathy. This gene was also asserted in relation to congenital myasthenic syndrome in 2015 (Belaya et al., PMID: 26133662), however a review of the phenotypes, molecular mechanism, and published assertions demonstrated that the disorders should be considered part of the same spectrum and thus assessed together. Over 50 variants (e.g. missense, in-frame indel, nonsense, frameshift, etc.) have been reported in humans since these initial reports. The most frequent variant is the c.79G>C (p.Asp27His) founder variant, with others being c.859C>T (p.Arg287Trp) and c.860G>A (p.Arg287Gln) (Sun et al. 2020, PMID: 30684953). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 Points): Variants in this gene have been reported in over 80 probands and at least 13 different publications, with four of those being evaluated in this curation (PMIDs: 23768512, 25770200, 27766311, 29437916). No strongly supportive segregation evidence was characterized among these publications. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with the loss or alteration of the GDP-mannose pyrophosphorylase B protein causing a dysfunctional early step in the N-glycosylation, O-mannosylation, and C-mannosylation pathways which includes alpha-dystroglycan (Rodriguez Cruz et al. 2016, PMID: 27147698). Although the congenital myasthenic syndrome probands show some additional neuromuscular phenotypes, it is likely that this is caused by disruption of other neuromuscular junction proteins' glycosylation. Summary of Experimental Data (2.5 Points): This gene-disease association is supported by several pieces of experimental evidence. As shown, *GMPPB* is known to have a critical role in the glycosylation pathway of alpha-dystroglycan which can have variably severe developmental consequences when disrupted. RT-PCR of human fetal and adult RNA tissues confirmed that the predominant isoform of *GMPPB* is strongly expressed in all tissues, particularly the skeletal muscle and brain. A zebrafish knockdown via a splice-blocking morpholino showed a variety of muscular and cranial phenotypes such as bent tails, altered skeletal muscle fibers, ocular phenotypes, slow movement, and reduced glycosylation of alpha-dystroglycan (Carss et al. 2013, PMID: 23768512). In summary, *GMPPB* is definitively associated with autosomal recessive myopathy caused by variation in *GMPPB*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0014140
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014142
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018144
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014142
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018940
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0018939
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014142
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014140
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014140
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: Cardiovascular complications, including long QT syndrome and cardiomyopathy, have been described, and awareness may allow surveillance and prompt management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GMPPB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021971.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 88 | 95 | |||
| missense | 5 | 27 | 167 | 5 | 204 | |
| nonsense | 7 | 1 | 1 | 9 | ||
| start loss | 0 | |||||
| frameshift | 12 | 9 | 21 | |||
| splice donor/acceptor (+/-2bp) | 1 | 10 | 3 | 14 | ||
| Total | 25 | 47 | 178 | 93 | 0 | 343 |
Highest pathogenic variant AF is 0.0009514399
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_068806.2 | 9 | MANE Select | |
| Ensembl | ENSP00000311130.6 | 9 | MANE Select | |
| RefSeq | NP_037466.3 | 8 | Standard | |
| Ensembl | ENSP00000309092.6 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gmppb | Danio rerio | Structure: skeletal muscle cell Quality: sparse abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fructose and mannose metabolism - Homo sapiens (human)
- Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
- Fructose intolerance, hereditary
- Fructose and Mannose Degradation
- Fructosuria
Biological Process
- GDP-mannose biosynthetic process
Molecular Function
- mannose-1-phosphate guanylyltransferase activity
- protein binding
- GTP binding
Cellular Component
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000308375
- Coding exons
- 8
- Length
- 7108
- Individuals with no LoFs
- 125714
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125744
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.02 | 205 | 250 | 0.819 | 0.0000152 | 2498 |
| Missense (PolyPhen) | 68 | 98.036 | 0.69362 | 1008 | ||
| Synonymous | -0.454 | 108 | 102 | 1.06 | 0.00000605 | 800 |
| Loss of Function | 1.28 | 12 | 17.8 | 0.674 | 8.10e-7 | 193 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000079 | 0.000070 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids. {ECO:0000250|UniProtKB:P0C5I2}.;
- Disease
- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A14 (MDDGA14) [MIM:615350]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with brain anomalies, eye malformations, and profound mental retardation. The disorder includes a severe form designated as Walker-Warburg syndrome and a less severe phenotype known as muscle-eye-brain disease. MDDGA14 features include increased muscle tone, microcephaly, cleft palate, feeding difficulties, severe muscle weakness, sensorineural hearing loss, cerebellar hypoplasia, ataxia, and retinal dysfunction. {ECO:0000269|PubMed:23768512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy congenital with mental retardation B14 (MDDGB14) [MIM:615351]: A congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. {ECO:0000269|PubMed:23768512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C14 (MDDGC14) [MIM:615352]: An autosomal recessive form of muscular dystrophy characterized by mild proximal muscle weakness with onset in early childhood. Some patients may have additional features, such as mild intellectual disability or seizures. {ECO:0000269|PubMed:23768512, ECO:0000269|PubMed:26310427, ECO:0000269|PubMed:28433477, ECO:0000269|PubMed:28478914}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.196
Intolerance Scores
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.56
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.976
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |