Investigating the Contribution of SOX17 Mutations to the Pathogenesis of Pulmonary Arterial Hypertension (360G-Wellcome-203762_Z_16_A)

Pulmonary arterial hypertension (PAH) is a rare fatal disease characterised by increased medial muscularisation of larger pulmonary arteries and neomuscularisation of small non-muscular arterioles, leading to obliteration of the vessel lumens. This increases the pulmonary arterial pressure and thus, the workload placed on the right ventricle, ultimately causing death by right ventricular failure. PAH is associated with endothelial dysfunction, namely increased permeability and apoptosis. Mutations in the gene encoding the Bone Morphogenetic Protein type II receptor, BMPR2, cause the majority of familial PAH cases and approximately 25% of apparently sporadic cases. Recently, we have co-ordinated a national DNA sequencing study of patients with idiopathic PAH to identify causal genetic mutations. Our study has identified that mutations in the gene, SOX17, are significantly associated with PAH in some IPAH patients. SOX17 is a transcription factor that is reported to control endothelial function during developmental angiogenesis, integrating with vascular endothelial growth factor signalling. We have identified a potential link with BMP signalling, whereby circulating BMP ligands that regulate endothelial stability induce the expression of SOX17. My project aims to explore the role of SOX17 in the pulmonary circulation and how SOX17 deficiency may cause dysregulated pulmonary vascular function.