MPI
protein-codingmannose phosphate isomerase
Gene summary
Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate and plays a critical role in maintaining the supply of D-mannose derivatives, which are required for most glycosylation reactions. Mutations in the MPI gene were found in patients with carbohydrate-deficient glycoprotein syndrome, type Ib. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: ClinGen
MPI was first reported in relation to autosomal recessive congenital disorder of glycosylation in 1998 (Niehues et al., PMID 9525984). Fourteen variants (missense, nonsense, frameshift, splice site) that have been reported in 10 probands in 7 publications (PMIDs 9525984, 10980531, 9585601, 11350186, 17945525, 33204592, 33098580) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Patients have a range of symptoms, including protein losing enteropathy, gastrointestinal involvement, hepatomegaly, hepatic fibrosis, and hypoglycemia. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by the biochemical function of MPI, which converts fructose-6-phosphate into mannose-6-phosphate, providing the necessary mannose-6-phosphate for glycosylation (PMID 9525984). Animal models deficient in MPI, including mouse and zebrafish, have defects in N-glycosylation consistent with patients with MPI-CDG (PMIDs 22899857, 24474243). In vitro assays in patient cells also support an N-glycosylation defect (PMID 22496445). In summary, there is definitive evidence supporting the relationship between MPI and autosomal recessive congenital disorder of glycosylation. 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 Congenital Disorders of Glycosylation Gene Curation Expert Panel on December 20, 2023 (SOP version 10). Additional contributions to this curation were made by UNC Biocuration Core and Counsyl.
Inheritance Pattern: AR
Disease ID:MONDO:0011257
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Gastrointestinal; Hematologic
Intervention: Biochemical; Hematologic
Rationale: Treatment with oral mannose can result in clinical improvement; Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery
Comments: Hepatic-metabolized agents should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MPI variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002435.3. 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 | 7 | 185 | 1 | 193 | ||
| missense | 2 | 18 | 117 | 8 | 145 | |
| nonsense | 7 | 17 | 1 | 25 | ||
| start loss | 2 | 2 | ||||
| frameshift | 31 | 55 | 1 | 87 | ||
| splice donor/acceptor (+/-2bp) | 1 | 28 | 2 | 31 | ||
| Total | 41 | 120 | 128 | 193 | 1 | 483 |
Highest pathogenic variant AF is 0.00026826328
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002426.1 | 8 | MANE Select | |
| Ensembl | ENSP00000318318.6 | 8 | MANE Select | |
| RefSeq | NP_001276084.1 | 7 | Standard | |
| RefSeq | NP_001276085.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mpi | Danio rerio | Structure: mandibular arch skeleton Quality: malformed 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
- cell wall mannoprotein biosynthetic process
- protein glycosylation
- GDP-mannose biosynthetic process
- mannose to fructose-6-phosphate metabolic process
Molecular Function
- mannose-6-phosphate isomerase activity
- zinc ion binding
Cellular Component
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000352410
- Coding exons
- 8
- Length
- 9453
- Individuals with no LoFs
- 125704
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 44
- Defined
- 125748
- p
- 0.000175
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.153 | 219 | 225 | 0.971 | 0.0000124 | 2766 |
| Missense (PolyPhen) | 70 | 73.437 | 0.9532 | 849 | ||
| Synonymous | 0.901 | 82 | 93.1 | 0.881 | 0.00000515 | 855 |
| Loss of Function | 1.03 | 13 | 17.7 | 0.735 | 8.62e-7 | 209 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.;
Recessive Scores
- pRec
- 0.622
Intolerance Scores
- LoFtool
- 0.265
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 42.06
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.757
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |