MPI-CDG

What is MPI?

MPI is the name of a gene that encodes an enzyme called mannose-6 phosphate isomerase (alternately phosphomannose isomerase, or PMI). MPI facilitates the interconversion of fructose 6-phosphate and mannose 6-phosphate. Mannose 6-phosphate is the starting material for all N-linked protein glycosylation production needs.

Orthologs of MPI are conserved in mice, zebrafish, flies, worms, budding yeast and fission yeast.

What does MPI do?

MPI was first characterized in budding yeast by Smith et al., 1992, where it was shown that GDP-mannose and dolichol-phosphate-mannose levels are dramatically reduced, as expected. As a result, PMI40 knockout yeast mutant cells require mannose supplementation in order to survive.

The MPI knockout mouse is lethal (DeRossi et al., 2006), which tends to be the rule in CDGs where complete loss of function of a CDG gene is lethal. Viable CDG mouse models tend to have so called hypomorphic mutations knocked in, which means there’s some residual CDG gene function. The authors concluded: “Our results in vitro suggest that mannose toxicity in Mpi(-/-) embryos is caused by Mannose-6-Phosphate accumulation, which inhibits glucose metabolism and depletes intracellular ATP. This was confirmed in E10.5 Mpi(-/-) embryos where Mannose-6-Phosphate increased more than 10 times, and ATP decreased by 50% compared with Mpi(+/+) littermates. Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles.”
Zebrafish model supports conserved disease progression and rescue of disease phenotypes by mannose supplementation but only if provided no later than 24 hours post fertilization (Chu et al., 2013).

Figure 3 from Chu et al., 2013 showing organism-wide abnormalities including small head, microphthalmia, pericardial edema, jaw defects and reduced liver size

Clinical presentation of MPI-CDG

MPI-CDG was referred to as CDG-1b. Patients with MPI-CDG do not have intellectual disability or neurological impairment, compared with most other Type I CDGs, especially PMM2-CDG. In the first published clinical report on MPI-CDG, Jaeken et al., 1998 noted that “MPI-CDG differs from most other described glycosylation disorders due to its lack of central nervous system involvement, and because it has treatment options besides supportive care. Supplementation with oral mannose has been shown to improve most symptoms of the disease.” 
Freeze et al., 1999 reviewed the 9 MPI-CDG patients who had been diagnosed at that time and provided n-of-1 patient biomarker data before and after mannose supplementation.

Figure 3 from Freeze et al., 1999 showing normalization of glycoprotein biomarkers ATIII nand albumin after 11 months of mannose supplementation therapy.

Beyond dietary mannose 

Janssen et al., 2014 showed that oral mannose supplementation can address the protein-losing enteropathy and coagulation abnormalities seen in MPI-CDG but it doesn’t address chronic liver wasting so a liver transplant is required for long-term survival. The MPI-CDG community needs therapeutic options other than surgery and organ transplantation.

As alluded to above, mannose supplementation during pregnancy in a MPI-CDG mouse model had an unexpected harmful effect (Sharma et al., 2014). What’s more, mannose supplementation has other unexpected side effects outside the context of congenital disorders of glycosylation, namely in cancer. (Gonzalez et al., 2018)

Yeast, worm, and fly MPI-CDG disease models are desperately needed, as well as a true genetic knockout zebrafish model (versus the morpholino knockdown model described in Chu et al., 2013). These preclinical disease models are necessary to advance the community beyond mannose supplementation as the standard of care. Once the tires have been kicked on MPI-CDG disease models with engineered patient mutations, it will be time to kick drug repurposing and genetic modifier screens into high gear. Experimental gene editing and antisense oligonucleotide approaches are warranted on a mutation by mutation basis. 

References

Chu J, Mir A, Gao N, Rosa S, Monson C, Sharma V, Steet R, Freeze HH, Lehrman MA, Sadler KC. (2013). A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation. Disease Models and Mechanisms. 6: 95-105.

DeRossi C, Bode L, Eklund EA, Zhang F, Davis JA, Westphal V, Wang L, Borowsky AD, Freeze HH. (2006). Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6 phosphate accumulation, toxicity, and embryonic lethality. Journal of Biological Chemistry. 281: 5916-27.

Freeze HH, Aebi M. (1999). Molecular basis of carbohydrate-deficient glycoprotein syndromes type I with normal phosphomannomutase activity. Biochimica Biophysica Acta. 1455: 167-178.

Gonzalez PS, O’Prey J, Cardaci S, Barthet VJA, Sakamaki JI, Beaumatin F, Roseweir A, Gay DM, Mackay G, Malviya G, Kania E, Ritchie S, Baudot AD, Zunino B, Mrowinska A, Nixon C, Ennis D, Hoyle A, Millan D, McNeish IA, Sansom OJ, Edwards J, Ryan KM. (2018). Mannose impairs tumour growth and enhances chemotherapy. Nature. 563: 719-723.

Jaeken J, Matthijs G, Saudubray JM, Dionisi-Vici C, Bertini E, de Lonlay P, Henri H, Carchon H, Schollen E, Van Schaftingen E. (1998). Phosphomannose isomerase deficiency: a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation. American Journal of Human Genetics. 62: 1535-9.

Janssen MC, de Kleine RH, van den Berg AP, Heijdra Y, van Scherpenzeel M, Lefeber DJ, Morava E. (2014). Successful liver transplantation and long-term follow-up in a patient with MPI-CDG. Pediatrics. 134: e279-283.

Sharma V, Nayak J, DeRossi C, Charbono A, Ichikawa M, Ng BG, Grajales-Esquivel E, Srivastava A, Wang L, He P, Scott DA, Russell J, Contreras E, Guess CM, Krajewski S, Del Rio-Tsonis K, Freeze HH. (2014). Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. FASEB Journal. 28: 1854-69.

Smith DJ, Proudfoot A, Friedli L, Klig LS, Paravicini G, Payton MA. (1992). PMI40, an intron-containing gene required for early steps in yeast mannosylation. Molecular and Cell Biology. 12: 2924-2930.

Sign up for the CDG Hub mailing list

Would you like to be contacted by (pick all that apply)