PCBD1 and diabetes: a novel player with direct implications for therapy. D. Simaite1, 2, J. Kofent1, M. Gong1,2, F. Rüschendorf1, S. Jia1, P. Arn3, K. Bentler4, C. Ellaway5, P. Kühnen6, G. F. Hoffmann7, N. Blau7,8, F. M. Spagnoli1, N. Hübner1, K. Raile2,6 1) Max Delbrück Center for Molecular Medicine, Berlin, Germany; 2) Experimental and Clinical Research Center, Berlin, Germany; 3) Nemours Childrens Clinic, Jacksonville, FL; 4) University of Minnesota Amplatz Children's Hospital, Minneapolis, MN; 5) Royal Alexandra Hospital for Children, Westmead, NSW, Australia; 6) Charité University Medicine, Berlin, Germany; 7) University Childrens Hospital, Heidelberg, Germany; 8) University Childrens Hospital, Zürich, Switzerland.

   Monogenic diabetes is a rare genetically and clinically heterogenic disease with mutations in more than 20 genes known to cause it in a dominant or recessive manner. Interestingly, several of these genes overlap with the susceptibility loci of polygenic type 2 diabetes (T2DM), suggesting that mutations in genes causing a rare disease can contribute to the development of the common disease. However, the genetic defects in many families with presumed monogenic diabetes still remain unclear. Identification of them would give us an insight in the pathogenesis mechanisms of not only monogenic diabetes but also of polygenic T2DM as well as might suggest new treatment strategies for both diseases. Here, we employed the whole-genome sequencing of a family with early-onset diabetes and identified a novel deletion in PCBD1, coding for a dimerization cofactor of HNF1A and HNF1B transcription factors, which have previously been shown to cause monogenic diabetes. Moreover, we identified three additional diabetic cases among the patients with neonatal hyperphenylalaninemia caused by the homozygous loss of function mutations in PCBD1. Interestingly, all these patients could change from insulin to oral antidiabetic drug therapy resulting in an improved glycemic control. Besides that, functional analysis showed Pcbd1 expression in the pancreas of Xenopus and mouse embryos from early specification onward, with enrichment in endocrine progenitor cells, suggesting an evolutionary conserved function. Furthermore, a morpholino-mediated knockdown in Xenopus revealed that Pcbd1 activity is required for a proper early pancreatic fate specification. The expression of Pcbd1 was also maintained in the mouse insulinoma cell line, however, transient Pcbd1 knockdown neither affected cell viability nor the expression of several genes important for insulin production and secretion. Therefore, it is likely that the reduced pancreatic beta cell progenitor pool might be responsible for the development of the disease. In summary, we provide not only genetic but also functional evidence that PCBD1 mutations can cause early-onset monogenic diabetes. Moreover, it can be treated with oral antidiabetic drugs instead of insulin resulting in a better outcome for the patients.

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