Novel phenotypes and genes in pseudoxanthoma elasticum-related soft tissue mineralization: results of an integrative approach

Soft tissue mineralization (STM) results from the perturbation of a delicate balance between calcification mediators, leading to ST destruction with important morbidity and mortality. The mechanisms underlying STM are however poorly understood, limiting precision medicine in and treatment of patients. Pseudoxanthoma elasticum (PXE), characterized by elastic fiber mineralization due to ABCC6 mutations, is considered a paradigm STM disorder. Initially thought to be a unique monogenic disorder, this perception changed when the PXE-like syndrome, caused by GGCX mutations, was identified. Since then, multiple overlapping phenotypes in the PXE spectrum have been described as well as an increasing number of genes involved – some as causal genes, others as an (partial) explanation for the immense clinical variability seen in these patients. We have chosen a systems biological approach to understand the underlying mechanisms which unite and distinguish these related phenotypes, by integrating techniques such as genomics (whole exome sequencing; WES), proteomics, transcriptomics and in silico computational biology. Using this approach we established a preliminary STM interactome with BMP2, TGFβ2 and Wnt-MSX2 as key cellular mediators. Complementary data on this interactome are gathered by whole transcriptome analysis of patient fibroblasts, which proves to be an efficient approach to identify unexpected STM signaling cascades. Together, this already provided a better understanding of many independent observations in STM over the last 30 years. Furthermore, WES of extreme phenotypes allowed us to identify several novel candidate modifier genes, among the most promising of which is e.g. the transcription factor VDR. Though many riddles of STM remain to be solved, our integrative stepwise approach has proven to be successful in expanding our knowledge of the mechanisms underlying STM, without losing sight of neither their interdependencies nor the global picture