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.