Abstract
Pathogenic variants in biglycan cause two divergent phenotypes: Meester-Loeys syndrome (MRLS) and X-linked spondyloepimetaphyseal dysplasia (SEMDX). The latter is characterized by a disproportionate short stature and caused by missense variants. MRLS, on the other hand, is a syndromic form of thoracic aortic aneurysm that is caused by loss-of-function variants. Intriguingly, MRLS patients with partial biglycan deletions present with a more severe skeletal phenotype. To date, discriminative pathomechanisms explaining why certain biglycan mutations cause MRLS and others SEMDX remain elusive. This PhD project aims to answer this research question using induced pluripotent stem cells (iPSCs) of both patient groups and their respective (isogenic) controls. IPSC-based disease modeling provides a unique opportunity for pathomechanistic investigation in a patient-, variant- and cell type-specific manner. After the creation of disease-relevant patient-derived iPSC-vascular smooth muscle cells and -chondrocytes, I will identify cell type-specific differences between MRLS and SEMDX using (1) functional assays tailored to existing pathomechanistic insights, and (2) hypothesis-free transcriptomic and proteomic approaches. Finally, I will investigate the mutational effect of partial biglycan deletions to establish a specific MRLS genotype-phenotype association.
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