Pathomechanistic study of biglycan mutations in aortopathy and skeletal dysplasia.

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, we identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with our observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Keywords:AORTAPATHY

Disciplines:Vascular diseases, Clinical genetics and molecular diagnostics, Medical genomics, Genetics