Z Gastroenterol 2016; 54 - FV03
DOI: 10.1055/s-0036-1586767

Identification and characterisation of a novel juvenile onset diabetes (JOD) gene using human pluripotent stem cells

A Illing 1, I Costa 2, A Lechel 1, Q Lin 3, T Seufferlein 1, A Kleger 1
  • 1Universitätsklinik, Ulm, Deutschland
  • 2Uniklinik, Aachen, Deutschland
  • 3Uniklinik Aachen, Innere Medizin 1, Aachen, Deutschland

Diabetes represents one of the major burdens in the 21st century with approx. 350 million people affected worldwide. Monogenic diabetes such as juvenile onset insulin-dependent diabetes (JOD) or maturity onset diabetes of the young (MODY) accounts for approximately 1 – 2% of diabetes cases and results from mutations that primarily reduce β-cell function. The identification of the genetic basis of these diabetes forms has translated into novel avenues of personalized medicine in the diabetes field, but only few of these genes have been identified to date. Based on published data, we hypothesize that a proportion of the genetic contribution to common diabetes (T1D and T2D) may be caused by rare monogenic variants/mutations missed by the current GWAS strategies targeting common variants. The current project reports on such a novel gene relevant as regulator of human pancreatic islet formation but also as a novel juvenile onset diabetes (JOD) gene. Using stage-specific genome wide profiling complemented with Chip-Seq data in differentiating human embryonic stem cells, we show that our gene binds and activates Nkx2.2, Nkx6.1 and Pdx1, all belonging to the core suite of isletogenesis transcription factors. Interestingly, this gene co-occupies the enhancer and promoter regions of the latter genes together with Foxa2, Pdx1 and Gata6. Finally, we engineered human embryonic stem cells with previously identified mutations in JOD patients. Directed differentiation studies of these cells shows an altered binding pattern of Nkx2.2, Nkx6.1 and Pdx1 finally leading to reduced amounts of monohormonal β-cells. This reduced target gene binding results from a limited zinc affinity, due to the mutation, that would be necessary as co-factor for gene binding. This platform not only allows personalised drug-testing but also sheds light on the mechanism how our JOD gene regulates pancreatic development and leads to diabetes in case of certain mutations in humans.