ESPE Abstracts (2014) 82 FC9.3

In Search for New Monogenic Diabetes Genes: PCBD1

Deimante Simaitea,b, Julia Kofenta, Maolian Gonga,b, Franz Rüschendorfa, Shiqi Jiaa, Pamela Arnc, Kristi Bentlerd, Carolyn Ellawaye, Peter Kühnenf, Georg Hoffmanng, Nenad Blaug,h, Francesca Spagnolia, Norbert Hübnera & Klemens Raileb,f


aMax Delbrück Center for Molecular Medicine, Berlin, Germany; bExperimental and Clinical Research Center, Berlin, Germany; cNemours Children’s Clinic, Jacksonville, Florida, USA; dAmplatz Children’s Hospital, University of Minnesota, Minneapolis, Minnesota, USA; eRoyal Alexandra Hospital for Children, Westmead, New South Wales, Australia; fCharité University Medicine, Berlin, Germany; gUniversity Children’s Hospital, Heidelberg, Germany; hUniversity Children’s Hospital, Zürich, Switzerland


Background: Mutations in more than 20 genes are described to cause monogenic diabetes. Nevertheless, numerous families with diabetes of unknown ethology and suspected genetic defect have no molecular diagnosis. This not only impedes our understanding of disease mechanisms but also prevents from predicting the clinical course of the patients and applying the pathogenesis-oriented treatment.

Objective: To identify novel gene(s), causing monogenic adolescent-onset diabetes.

Methods: Whole-genome sequencing (WGS), linkage analysis, Sanger sequencing, systematic recall of the patients present in BIODEF (International Database of Tetrahydrobiopterin Deficiencies) and gene expression studies in frog and mouse embryos and mouse insulinoma cell line were applied to identify, validate and characterize the novel disease-causing gene.

Results: We identified a novel frameshift deletion in PCBD1 (pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha), a gene that has recently been suggested as a possible cause of diabetes. Subsequent reexamination of the patients with mild transient neonatal hyperphenylalaninemia due to homozygous mutations in PCBD1 included in the BIODEF database revealed three additional cases that developed HNF1A-like diabetes in puberty, indicating an early pancreatic beta cell failure. We found that Pcbd1 was not only expressed in the developing pancreas of both Xenopus and mouse embryos, but was enriched in endocrine progenitors and colocalized with insulin, too. Notably, gene knockdown approach in Xenopus showed that early pancreatic fate specification was dependent on Pcbd1 activity within the endoderm.

Conclusions: We provide the first genetic evidence that PCBD1 mutations cause non-autoimmune HNF1A-like adolescent-onset diabetes which can be treated with sulphonylureas instead of insulin. Moreover, patients at risk can be indicated through the newborn screening for phenylketonuria. Furthermore, our findings suggest Pcbd1 role in the pancreatic progenitor pool establishment during embryogenesis, which might lead to reduced pancreatic beta cell mass in the adult.