A mouse model with PMM2-CDG

By Fiona Waddell
Request a scientific publication at publicationscdg@gmail.com

Jin Shengfang, PhD, Senior Director, Biology of Agios Pharmaceuticals in the USA, and her team created a mouse model with CDG-PMMr, the most common Congenital Disorder of Glycosylation. This subtype is caused by mutations in the enzyme phosphomannomutase 2 (PMM2), which is necessary to conjugate the sugar mannose to GDP, whereby the sugar is available for the build-up of sugar chains. When this enzyme is not functional, the sugar chains in proteins may not be fully built and a problem arises in the glycosylation; A CDG.

PMM2-CDG has no therapy and there are no models to test new treatments, but Shengfang and her team generated mice with the R137H and F115L mutations in PMM2 that correspond to the most prevalent human alleles of R14H and F119L, a particular variant of a gene, found in patients with PMM2-CDG. Many of these mice died prenatally, while survivors had significantly stunted growth. These animals and cells showed protein glycosylation deficiencies which are similar to those seen in patients with PMM2-CDG.

The imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in the mouse model and in PMM2-CDG patients. They both displayed reductions in PMM activity, GDP-mannose, lipid-linked oligosaccharide (known as a glycan) precursor and total cellular protein glycosylation along with hypoglycosylation of a new endogenous biomarker, the glycoprotein 130.

The mouse model and the biomarker that is discovered is created to try to understand basic biology in glycosylation and mechanisms of CDG disease. The discovery sheds new light on PMM2-CDG in humans and provedes essential tools to test potential therapies for this, up to now, untreatable disease. To advance the science in this field and to help enable the community to find a cure for this devastating disease, Shengfang and her team have shared their research findings in detail with Human Molecular Genetics (it is available in open acces here). They are making plans to make this model broadly available via depositing in JAX laboratory.

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