Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In the last 20+ years a total of 9 genetic loci have been associated with HI, however, in approximately 40-50% of cases a genetic cause is not identified. The elucidation of the molecular mechanisms responsible for HI is of great importance to guide the development of novel therapies and eventually, a cure. Building on the success of the previous cycles of this award, we propose a comprehensive approach to examine the mechanisms of disease for two novel forms of HI that we have previously mapped to specific genomic loci by linkage analysis and whole exome sequencing. In addition, we propose a broad discovery effort for novel mechanisms of disease by performing deep genotyping and phenotyping of both individuals and isolated islets in cases with negative genetic testing on constitutional DNA. Our overall hypothesis is that genetic testing negative HI cases can be explained by novel genetic loci encompassing factors important for -cell function and by somatic mutations of known HI genes. To test this hypothesis, we propose two aims: to examine the mechanisms responsible for dysregulated insulin secretion by novel genetic loci identified in families with dominantly-inherited HI: Hexokinase 1 and PASK; to identify the role of post-zigotic mutations in HI; and to continue our discovery efforts through a comprehensive approach to examine genomics and functionomics of HI by deep genotyping and functional evaluations of affected individuals and their pancreatic islets. This study will expand our understanding of the molecular genetics and pathophysiology of HI and will facilitate the identification of new genetic causes and potential new therapeutic targets for this devastating disease. The discovery of novel HI loci may lead to a better understanding of the mechanisms regulating insulin secretion and may benefit the development of new therapies not only for HI, but also for diabetes.
Relevance Congenital hyperinsulinism is a severe genetic disorder associated with high rates of neurodevelopmental impairment. This study will expand our understanding of the pathophysiology of hyperinsulinism and will facilitate the identification of new molecular mechanisms of disease and potential new therapeutic targets for this devastating disease. This study will improve our understanding of the mechanisms regulating insulin secretion in health and disease, and may benefit the development of new therapies not only for HI, but also for diabetes.
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