title: A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2.
abstract: The most common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations in Pmm2 that correspond to the most prevalent alleles found in patients with PMM2-CDG. Many Pmm2R137H/F115Lmice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3 and acid-labile subunit, along with antithrombin III, were all deficient in Pmm2R137H/F115Lmice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. Both Pmm2R137H/F115Lmouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, guanosine diphosphate mannose, lipid-linked oligosaccharide precursor and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG, in vitro assays and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease.
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Barden
authors.initials: B
authors.lastname: Chan
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Clasquin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Gromoslaw A
authors.initials: GA
authors.lastname: Smolen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Histen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Powe
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Cancer Research Center, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai 200131, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Lu
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai 200131, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai 200131, China Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
authors.affiliation: HD Biosciences Co., Ltd, Shanghai 201201, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Yan
authors.affiliation: HD Biosciences Co., Ltd, Shanghai 201201, China.
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: LGC Genomics, Beverly, MA 01915, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Thompson
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Singleton
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Silverman
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA.
authors.forename: Shin-San Michael
authors.initials: SM
authors.lastname: Su
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA Shengfang.Jin@agios.com.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
mesh_terms: D000818:Animals; D015415:Biomarkers; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D008358:Mannose / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics*
chemical_list: D015415:Biomarkers; C494200:Il6st protein, mouse; D050822:Cytokine Receptor gp130; D017875:Phosphotransferases (Phosphomutases); C513491:Pmm2 protein, mouse; D008358:Mannose