Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice

Abstract

Patients with congenital disorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomerase (MPI) that impair glycosylation and lead to stunted growth, liver dysfunction, coagulopathy, hypoglycemia, and intestinal abnormalities. Mannose supplements correct hypoglycosylation and most symptoms by providing mannose-6-P (Man-6-P) via hexokinase. We generated viable Mpi hypomorphic mice with residual enzymatic activity comparable to that of patients, but surprisingly, these mice appeared completely normal except for modest (~15%) embryonic lethality. To overcome this lethality, pregnant dams were provided 1-2% mannose in their drinking water. However, mannose further reduced litter size and survival to weaning by 40 and 66%, respectively. Moreover, ~50% of survivors developed eye defects beginning around midgestation. Mannose started at birth also led to eye defects but had no effect when started after eye development was complete. Man-6-P and related metabolites accumulated in the affected adult eye and in developing embryos and placentas. Our results demonstrate that disturbing mannose metabolic flux in mice, especially during embryonic development, induces a highly specific, unanticipated pathological state. It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious.

Mannose metabolism: More than meets the eye

“…A viable Mpi -deficient mouse was generated by knocking-in a known MPI-CDG patient mutation causing a Y255C substitution [4]. This was shown to lead to a predicted 14% MPI activity comparable to 7% seen in the patient fibroblasts.…”

“…Reducing mannose in the water to 1% or 2% led to live births. However, there was a dose dependent toxic effect on liter size and survival to weaning [4]. …”

“…Approximately 50% pups born to dams supplemented with 1% and 2% mannose, developed ocular defects, mainly affecting the lens and amacrine cells of the retina [4] (fig. 4).…”

“…This might also be a bad decision. The 1.5-fold increase in plasma mannose seen in Mpi Y255C/Y255C dams given 1% mannose suggests that there is a narrow window of mannose metabolic flux, which can determine life, death or gross eye malformations [4]. It is unknown whether the results seen in mice would apply to humans.…”

“…Mannose can be a life saving therapeutic and a non-antibiotic treatment for selected bacterial infections [3], but in other situations it can be lethal [4] or teratogenic [5], underscoring the importance of stringent regulation of mannose metabolism. In this review, we will discuss mannose origins, metabolism, fate in cells, animals and humans, and its therapeutic applications.…”