title: The normal phenotype of Pmm1-deficient mice suggests that Pmm1 is not essential for normal mouse development.
abstract: Phosphomannomutases (PMMs) are crucial for the glycosylation of glycoproteins. In humans, two highly conserved PMMs exist: PMM1 and PMM2. In vitro both enzymes are able to convert mannose-6-phosphate (mannose-6-P) into mannose-1-P, the key starting compound for glycan biosynthesis. However, only mutations causing a deficiency in PMM2 cause hypoglycosylation, leading to the most frequent type of the congenital disorders of glycosylation (CDG): CDG-Ia. PMM1 is as yet not associated with any disease, and its physiological role has remained unclear. We generated a mouse deficient in Pmm1 activity and documented the expression pattern of murine Pmm1 to unravel its biological role. The expression pattern suggested an involvement of Pmm1 in (neural) development and endocrine regulation. Surprisingly, Pmm1 knockout mice were viable, developed normally, and did not reveal any obvious phenotypic alteration up to adulthood. The macroscopic and microscopic anatomy of all major organs, as well as animal behavior, appeared to be normal. Likewise, lectin histochemistry did not demonstrate an altered glycosylation pattern in tissues. It is especially striking that Pmm1, despite an almost complete overlap of its expression with Pmm2, e.g., in the developing brain, is apparently unable to compensate for deficient Pmm2 activity in CDG-Ia patients. Together, these data point to a (developmental) function independent of mannose-1-P synthesis, whereby the normal knockout phenotype, despite the stringent conservation in phylogeny, could be explained by a critical function under as-yet-unidentified challenge conditions.
authors.affiliation: Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Cromphout
authors.forename: W
authors.initials: W
authors.lastname: Vleugels
authors.forename: L
authors.initials: L
authors.lastname: Heykants
authors.forename: E
authors.initials: E
authors.lastname: Schollen
authors.forename: L
authors.initials: L
authors.lastname: Keldermans
authors.forename: R
authors.initials: R
authors.lastname: Sciot
authors.forename: R
authors.initials: R
authors.lastname: D'Hooge
authors.forename: P P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: K
authors.initials: K
authors.lastname: von Figura
authors.forename: D
authors.initials: D
authors.lastname: Hartmann
authors.forename: C
authors.initials: C
authors.lastname: Körner
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007527:Isoenzymes; D037102:Lectins; D017875:Phosphotransferases (Phosphomutases); C052799:phosphomannomutase