title: 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.
authors.affiliation: 2Sanford-Burnham Medical Research Institute (SBMRI), 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. hudson@sanfordburnham.org.
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.forename: Jonamani
authors.initials: J
authors.lastname: Nayak
authors.forename: Charles
authors.initials: C
authors.lastname: DeRossi
authors.forename: Adriana
authors.initials: A
authors.lastname: Charbono
authors.forename: Mie
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Erika
authors.initials: E
authors.lastname: Grajales-Esquivel
authors.forename: Anand
authors.initials: A
authors.lastname: Srivastava
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Joseph
authors.initials: J
authors.lastname: Russell
authors.forename: Emily
authors.initials: E
authors.lastname: Contreras
authors.forename: Cherise M
authors.initials: CM
authors.lastname: Guess
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Katia
authors.initials: K
authors.lastname: Del Rio-Tsonis
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000818:Animals; D001766:Blindness / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D018981:Congenital Disorders of Glycosylation / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005123:Eye / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008358:Mannose / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D008359:Mannose-6-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism*; D008360:Mannosephosphates / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010920:Placenta / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy
chemical_list: D008360:Mannosephosphates; C027693:mannose-6-phosphate; D008359:Mannose-6-Phosphate Isomerase; D008358:Mannose
keywords: MPI-CDG; congenital disorder of glycosylation; eye defects; lens