Non-coding mutations in congenital hyperinsulinism: deciphering the role of gene dysregulation in human disease

This research will use novel insights from genomic analysis of individuals with congenital hyperinsulinism to provide new mechanistic understanding of the regulation of insulin secretion. Through preliminary studies I have identified non-coding mutations that affect the regulation of HK1, a housekeeping gene which is silenced within the beta-cell. These mutations pinpoint the first element to be discovered that regulates beta-cell specific silencing and highlights the role of ‘disallowed’ genes in pathophysiology. To discover further regulatory mutations affecting the expression of a beta-cell ‘disallowed’ gene I will integrate genomic data with epigenomic annotation in my unique cohort of ~2000 hyperinsulinism patients with known causes excluded. I will study the impact of mutations in affected pancreatic tissue to gain insights into 1) the mechanism(s) by which they disrupt insulin-secretion and 2) the regulatory networks that are critical for maintaining tissue-specific suppression of genes. The results from these studies may be leveraged to discover novel targets to better treat hyperinsulinism and will improve knowledge of the role of the non-coding genome. This will be important for genetic discovery in other monogenic conditions where the major focus has been on the discovery of coding mutations in genes highly expressed within the disease tissue.