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Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice
Author(s) -
Sharma Vandana,
Nayak Jonamani,
DeRossi Charles,
Charbono Adriana,
Ichikawa Mie,
Ng Bobby G.,
GrajalesEsquivel Erika,
Srivastava Anand,
Wang Ling,
He Ping,
Scott David A.,
Russell Joseph,
Contreras Emily,
Guess Cherise M.,
Krajewski Stan,
RioTsonis Katia Del,
Freeze Hudson H.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-245514
Subject(s) - mannose , fetus , embryo , gestation , pregnancy , embryonic stem cell , biology , haploinsufficiency , hide and seek , medicine , glycosylation , weaning , endocrinology , phenotype , andrology , biochemistry , microbiology and biotechnology , genetics , internet privacy , gene , computer science
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 hypo‐glycosylation and most symptoms by providing man‐nose‐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.—Sharma, V., Nayak, J., DeRossi, C., Charbono, A., Ichikawa, M., Ng, B. G., Grajales‐Esquivel, E., Srivastava, A., Wang, L., He, P., Scott, D. A., Russell, J., Contreras, E., Guess, C. M., Krajewski, S., Del Rio‐Tsonis, K., Freeze, H. H. Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. FASEB J. 28, 1854–1869 (2014). www.fasebj.org