# A hypomorphic Mpi mutation unlocks an in vivo tool for studying global N-glycosylation deficiency

## TL;DR

A new mouse model with a weakened Mpi gene helps study the effects of reduced N-glycosylation across multiple body systems.

## Contribution

A hypomorphic Mpi mutation provides a viable in vivo model for global N-glycosylation deficiency.

## Key findings

- The hypomorphic Mpi mutation causes a multisystemic phenotype in mice.
- Mannose rescues the phenotype and increases unoccupied N-glycan sites by 500%.
- This model mimics inborn glycosylation disorders and allows tissue-specific targeting.

## Abstract

Glycans are one of the 4 major macromolecules essential for life and are the most abundant family of organic molecules. However, in contrast with DNA and RNA, glycan structures have no template; this results in limited tools to study this challenging macromolecule with a diversity of glycan structures. A central bottleneck in studying glycosylation in vivo is that inhibitors and complete KOs are lethal. In a forward genetic screen, we identified a viable, hypomorphic mutation at a conserved site in mannose phosphate isomerase (Mpi) that causes a multisystemic phenotype affecting RBCs, liver, stomach, intestines, skin, size, fat, and fluid balance in mice. The phenotype could be rescued with mannose. Analyses of glycopeptides in mice with this mutation showed a 500% increase in unoccupied N-glycan sites. This is equivalent to a “glycan knockdown,” which would be useful for examining the role of glycans in biology and disease. Therefore, we report an in vivo tool to study global N-glycosylation deficiency with tissue-specific targeting and a rescue mechanism with mannose.

A hypomorphic Mpi mutation mimics an inborn glycosylation disorder, enabling future in vivo studies that require global N-glycosylation deficiency.