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. FASEB J. 2014 Apr 28(4):1854-69. doi: 10.1096/fj.13-245514.
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.