Monogenic forms of juvenile onset diabetes: towards novel insights in beta cell development, function and survival – MONODIA-POP

A small subset of juvenile onset insulin-treated diabetes (JOD) is caused by single gene mutations, contrasting with the general multifactorial inheritance of common diabetes. Several genes responsible for monogenic diabetes have been identified to date, and these affect ß-cell development, function and survival. The overall aim of this project is to identify and genetically characterize new monogenic entities of JOD and perform in-depth functional studies of these genes. The unique approach of this joint proposal is fostered by two partners having complementary track records in human genetics and functional biology. In the first stage, we will extend ongoing genetic studies of highly selected patients and families enriched in monogenic forms of diabetes to identify causative genes. We will perform extended large-scale re-sequencing of selected genes emerging from our exome sequencing data to genetically validate them, as well as of already known monogenic diabetes genes, in a large collection of 1000 JOD patients and controls. Thereby, we will identify monogenic causative mutations in these genes depending on the population, familial structure and clinical characteristics of patients. This will provide for the first time a reliable estimation of monogenic contributions to JOD in various settings. In preliminary studies, we have already identified several genes with monogenic contributions, as well as new mutations in previously reported genes, validating the power of our genetic strategy. In the second stage, starting simultaneously, we will perform in-depth functional studies of selected groups of these genes, starting with two genes: one gene (X) that we have previously identified as mutated in a new form of monogenic diabetes (homozygous mutated status: neonatal diabetes, heterozygous status: early-onset type 2 diabetes), and one gene (Y) that we recently validated as a monogenic diabetes gene with the identification of 7 new mutations in 8 unrelated JOD patients. First, we will extend functional data that characterize gene X using a human embryonic stem cell-derived b-cell platform. Second, we will study the specific functions of gene Y using a state-of-the-art phenotyping model, patient-specific induced pluripotent stem cells (hiPSCs) and genome-edited human embryonic stem cells (hESCs). The latter will be differentiated into pancreatic ß-cells for detailed functional analyses. Third, we will create the newly identified mutations in these genes by genomic editing in hESCs using an iCRISPR platform. Thus, we will develop a whole patient-specific cell-bank for detailed cellular investigations aiming to i) model diabetes in a dish to identify the molecular basis of the disease, ii) address novel therapeutic possibilities and iii) define a complete molecular network essential for endocrine pancreatic development as well as ß-cell function and maintenance. This study will establish the basis for true “personalized medicine” in diabetes therapy.