Characterisation of novel mutations in Steroid Receptor Coactivator 1 (360G-Wellcome-203513_Z_16_Z)

Steroid Receptor Coactivator-1 (SRC-1) is coactivator for various transcription factors (TFs) and nuclear hormone receptors (NRs). In rodents, SRC-1 plays a role in the regulation of energy balance and glucose homeostasis by activating ligand-bound nrs and TFs. We have recently identified 15 novel mutations in this molecule using whole exome sequencing and targeted resequencing of 2548 patients with severe early onset obesity (Genetics of Obesity Study: GOOS). In addition to obesity, these patients have other symptoms, including disproportionate insulin resistance and chronic diarrhoea. We hypothesise that human SRC-1 mutations directly impair the interaction with pSTAT3 to cause severe obesity, and impair NR-mediated gene expression, to cause insulin resistance and intestinal dysfunction. I propose to undertake the detailed functional and clinical characterisation of SRC-1 mutations. I will use HEK-293 cells to characterise the functional consequences of SRC-1 mutations, particularly focusing on their interaction with STAT3 and NRs. Patients will be invited to take part in clinical studies in which we will assess energy and glucose homeostasis, body composition and the circulation of bile salts. This work will improve our understanding of obesity, and shed light on mechanisms underlying patients’ symptoms to inform further work including interventional studies.