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Grant Award 017

Principal investigator: Stella Mitrani-Rosenbaum, PhD
Abbreviated Title of Research Proposal: In vitro and in vivo models for HIBM

Project Summary: Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, and a typical muscle pathology, including rimmed vacuoles and filamentous inclusions. The prototype HIBM is a form of the disease particularly frequent in Middle Eastern Jews presenting an additional unique feature, the sparing of the quadriceps. The gene responsible for the disease, which encodes the enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosanine kinase (GNE), was identified in our laboratory and found to carry a homozygous missense mutation in all Middle Eastern HIBM patients, while other patients worldwide have usually different mutations in the same gene. GNE is the key enzyme in sialic acid biosynthesis, which is involved in a variety of biological interactions, such as cell adhesion and migration.

In order to understand the pivotal role of GNE in the onset and progression of HIBM, we will introduce the most prominent human mutations identified in the GNE gene of HIBM patients in already available murine GNE-deficient embryonic stem cells. These cells will be analyzed morphologically and biochemically and will be further used to generate transgenic mice with GNE mutations in an endogenous GNE-free in vivo system. In addition, we will generate a mouse where the GNE gene could be switched off only in muscle tissue.

We anticipate that these studies will contribute to unravel the function of GNE and sialic acid metabolism in particular in muscle cells and reveal possible pathogenic mechanisms leading to HIBM. In addition, this animal model could be used for the assessment of therapeutic approaches.