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Molecular and Cellular Biology, August 2006, p. 5621-5635, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.02357-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Normal Phenotype of Pmm1-Deficient Mice Suggests that Pmm1 Is Not Essential for Normal Mouse Development

Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium,¹ Department of Pathology, Katholieke Universiteit Leuven, Leuven, Belgium,² Laboratory of Biological Psychology, Department of Psychology, Katholieke Universiteit Leuven, Leuven, Belgium,³ Laboratory of Neurochemistry and Behavior, Born-Bunge Institute, University of Antwerp, Antwerp, Belgium,⁴ Biochemistry II, University of Goettingen, Goettingen, Germany,⁵ Center for Human Genetics and Flanders Interuniversity Institute for Biotechnology, VIB4, Katholieke Universiteit Leuven, Leuven, Belgium,⁶ Universitätskinderklinik, Uni-Heidelberg, Heidelberg, Germany⁷

Received 10 December 2005/ Returned for modification 26 February 2006/ Accepted 25 April 2006

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.

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