Alternative titles; symbols
HGNC Approved Gene Symbol: MPI
SNOMEDCT: 1231141008;
Cytogenetic location: 15q24.1-q24.2 Genomic coordinates (GRCh38): 15:74,890,042-74,902,219 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.1-q24.2 | Congenital disorder of glycosylation, type Ib | 602579 | Autosomal recessive | 3 |
Mannosephosphate isomerase (MPI), also known as phosphomannose isomerase (PMI; EC 5.3.1.8), 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 (Proudfoot et al., 1994).
Proudfoot et al. (1994) purified human phosphomannose isomerase from placenta tissue. The authors used sequence information obtained from internal fragments of the protein to design degenerate oligonucleotides which were used to amplify a fragment of the PMI cDNA. Using this fragment to screen a human testis cDNA library, Proudfoot et al. (1994) isolated a full-length PMI cDNA. The PMI gene encodes a predicted 423-amino acid polypeptide. Northern blot analysis detected a single 1.8-kb PMI mRNA in all tissues tested, with the highest levels in heart, brain, and skeletal muscle. Recombinant PMI expressed in E. coli had very similar activity to the native enzyme.
Gonzalez et al. (2018) reported that the mannosaccharide mannose causes growth retardation in several tumor types in vitro, and enhances cell death in response to major forms of chemotherapy. Gonzalez et al. (2018) then showed that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of antiapoptotic proteins of the Bcl2 (151430) family, leading to sensitization to cell death. Gonzalez et al. (2018) further showed that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA interference-mediated depletion of the enzyme. In addition, Gonzalez et al. (2018) used tissue microarrays to show that PMI levels also vary greatly between different patients and different tumor types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. The authors suggested that the administration of mannose could be a simple, safe, and selective therapy in the treatment of cancer, and could be applicable to multiple tumor types.
Schollen et al. (2000) determined that the MPI gene contains 8 exons and spans 5 kb.
By human-mouse cell hybridization, Shows (1972) concluded that mannosephosphate isomerase and pyruvate kinase-3 (PK3; 179050) are syntenic. By cell hybridization studies, Van Heyningen et al. (1975) found that the MPI and PK3 loci are on chromosome 15. The murine Mpi gene is located on mouse chromosome 9 in the same linkage group as the gene for the LDL receptor (LDLR; 606945) (Frank et al., 1989), which is on human chromosome 19. Human chromosome 19 carries glucosephosphate isomerase (GPI; 172400). These genes may have had a common evolutionary origin but developed different specificities in the evolutionary lines of the 2 species.
In a patient with carbohydrate-deficient glycoprotein syndrome type Ib (CDG Ib, CDG1B; 602579), Niehues et al. (1998) identified a heterozygous mutation in the MPI gene (154550.0001). Schollen et al. (2000) identified a second mutation (154550.0004) in this patient, confirming compound heterozygosity and autosomal recessive inheritance. The mutation resulted in an unstable transcript and was barely detectable at the mRNA level. The findings emphasized the importance of mutation analysis at the genomic DNA level.
In a patient with CDG Ib, Jaeken et al. (1998) identified compound heterozygosity for 2 mutations in the MPI gene (154550.0002, 154550.0003).
Schollen et al. (2000) identified 8 different mutations in the MPI gene, including 7 novel mutations, in 7 patients with confirmed phosphomannose isomerase deficiency, including a patient previously reported by Niehues et al. (1998).
Vuillaumier-Barrot et al. (2002) found that the protein-losing enteropathy-hepatic fibrosis syndrome described in the Saguenay-Lac-Saint-Jean region of Quebec by Pelletier et al. (1986) is caused by an arg295-to-his mutation in the MPI gene (R295H; 154550.0005), and is therefore a form of CDG Ib.
McMorris et al. (1973) mapped the MPI gene to chromosome 7 and the GPI gene to chromosome 19; the mapping of the MPI gene to chromosome 7 was later retracted (Ruddle and McMorris, 1975).
In a patient with congenital disorder of glycosylation type Ib (CDG1B; 602579), Niehues et al. (1998) identified a heterozygous 656G-A transition in the MPI gene, resulting in an arg219-to-gln (R219Q) substitution. The patient presented at age 11 months with diarrhea and vomiting, protein-losing enteropathy, recurrent thrombotic episodes, and life-threatening gastrointestinal bleeding. There was no psychomotor retardation. Treatment with oral mannose resulted in clinical improvement. The patient was heterozygous for the R219Q mutation, which was inherited from the father. By genome sequencing in the patient previously reported by Niehues et al. (1998), Schollen et al. (2000) identified a 1-bp insertion in exon 3 of the MPI gene (116insC; 154550.0004) on the maternal allele, confirming compound heterozygosity. The mutation resulted in an unstable transcript, barely detectable at the mRNA level. The authors emphasized the importance of mutation analysis at the genomic DNA level.
In a patient with congenital disorder of glycosylation type Ib (CDG1B; 602579), Jaeken et al. (1998) identified compound heterozygosity for 2 mutations in the MPI gene: a 304C-T transition resulting in a ser102-to-leu (S102L) substitution, and a 413T-C transition resulting in a met138-to-thr (M138T) substitution (154550.0003). Both mutations involve highly conserved residues and are situated near the active site as determined by x-ray crystallography.
For discussion of the met138-to-thr (M138T) mutation in the MPI gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type Ib (CDG1B; 602579) by Jaeken et al. (1998), see 154550.0002.
For discussion of the 1-bp insertion in the MPI gene (116insC) that was found in compound heterozygosity in a patient with congenital disorder of glycosylation type Ib (CDG1B; 602579) by Schollen et al. (2000), see 154550.0001.
Pelletier et al. (1986) described a fatal syndrome of protein-losing enteropathy and congenital hepatic fibrosis in the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec. Clinically it resembled congenital disorder of glycosylation type Ib (CDG1B; 602579), with intractable diarrhea, hypoglycemia, hepatomegaly, vomiting, and malnutrition. For this reason, Vuillaumier-Barrot et al. (2002) studied PMI activity in leukocytes of 3 parents of 2 of the affected Canadian children. All 3 showed partial deficiency of leukocyte PMI activity and were heterozygous for an 884G-A transition in exon 7 of the MPI gene, resulting in an arg295-to-his (R295H) mutation. A patient newly diagnosed with CDG Ib from Nantes in Brittany, France, with the same clinical syndrome was found to be homozygous for the R295H mutation and also for nearby polymorphic markers. An identical variant was found for each marker on at least one chromosome of each of the SLSJ parents, consistent with migration from Brittany to Quebec.
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Chern, C. J., Kennett, R., Engel, E., Mellman, W. J., Croce, C. M. Assignment of the structural genes for the alpha subunit of hexosaminidase A, mannosephosphate isomerase and pyruvate kinase to the region q22-qter of human chromosome 15. Somat. Cell Genet. 3: 553-560, 1977. [PubMed: 341373] [Full Text: https://doi.org/10.1007/BF01539065]
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Pelletier, V. A., Galeano, N., Brochu, P., Morin, C. L., Weber, A. M., Roy, C. C. Secretory diarrhea with protein-losing enteropathy, enterocolitis cystica superficialis, intestinal lymphangiectasia, and congenital hepatic fibrosis: a new syndrome. J. Pediat. 108: 61-65, 1986. [PubMed: 3080572] [Full Text: https://doi.org/10.1016/s0022-3476(86)80769-7]
Proudfoot, A. E. I., Turcatti, G., Wells, T. N. C., Payton, M. A., Smith, D. J. Purification, cDNA cloning and heterologous expression of human phosphomannose isomerase. Europ. J. Biochem. 219: 415-423, 1994. [PubMed: 8307007] [Full Text: https://doi.org/10.1111/j.1432-1033.1994.tb19954.x]
Ritter, H., Friedrichson, U., Schmitt, J. Genetic variation of mannose phosphate isomerase in man. Humangenetik 22: 261-262, 1974.
Ruddle, F. H., McMorris, F. A. Assignment of mannose phosphate isomerase to human chromosome 7: a retraction. Cytogenet. Cell Genet. 14: 418-420, 1975. Note: Also in Birth Defects Orig. Art. Ser. 11(3): 248-250, 1975. [PubMed: 1088818] [Full Text: https://doi.org/10.1159/000130396]
Schollen, E., Dorland, L., de Koning, T. J., Van Diggelen, O. P., Huijmans, J. G. M., Marquardt, T., Babovic-Vuksanovic, D., Patterson, M., Imtiaz, F., Winchester, B., Adamowicz, M., Pronicka, E., Freeze, H., Matthijs, G. Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib). Hum. Mutat. 16: 247-252, 2000. [PubMed: 10980531] [Full Text: https://doi.org/10.1002/1098-1004(200009)16:3<247::AID-HUMU7>3.0.CO;2-A]
Shows, T. B. Linkage of loci for human pyruvate kinase and mannosephosphate isomerase in somatic cell hybrids. (Abstract) Am. J. Hum. Genet. 24: 13A only, 1972.
Van Heyningen, V., Bobrow, M., Bodmer, W. F., Gardiner, S. E., Povey, S., Hopkinson, D. A. Chromosome assignment of some human enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate isomerase and pyruvate kinase to 15 and probably, esterase D to 13. Ann. Hum. Genet. 38: 295-303, 1975. [PubMed: 1137344] [Full Text: https://doi.org/10.1111/j.1469-1809.1975.tb00613.x]
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