BBB Seminar: Marion Kusche-Gullberg

Marion Kusche-Gullberg,
Department of Biomedicine, University of Bergen

Multiple Hereditary Exostoses (MHE) is an inheritable autosomal dominant bone disorder characterized by the presence of cartilage capped bony outgrowths, exostoses (osteochondromas). The majority of the exostoses are found in bones that develop from cartilage, especially the long bones of the extremities. Two proteins are known to be mutated in MHE patients: Exostosin 1 and 2, encoded by the EXT1 and EXT2 genes, respectively. Both EXT1 and EXT2 encode glycosyltransferases involved in heparan sulfate biosynthesis. The mechanism by which exostosis develops is poorly understood but mutations in either EXT1 or EXT2 and the resulting reduction or absence of heparan sulfate in the exostosis cartilage cap has been implicated in disturbed signaling response in exostosis chondrocytes.

Heparan sulfate is a polysaccharide that is closely related to heparin. Heparan sulfates are ubiquitously expressed in all tissues, where they function as adhesion molecules and co-receptors. Thus, they modulate cell-matrix interactions and growth factor signaling.

We have studied the individual functions of the EXT1 and EXT2 proteins in heparan sulfate chain elongation and have previously shown that mouse embryonic fibroblasts with a gene trap mutation in EXT1 have substantially reduced heparan sulfate chain length. We have used these fibroblasts to investigate the functional consequences of the EXT1 mutation for heparan sulfate-dependent growth factor signaling and for cell interactions with the extracellular matrix.

Chair: Rolf Kåre Reed, Department of Biomedicine