Recessive mutations in PCBD1 cause a new type of early-onset diabetes

  1. Klemens Raile1,11,*
  1. 1Experimental and Clinical Research Center (ECRC), an institutional cooperation between Charité Medical Faculty and MDC, Berlin, Berlin 13125, Germany
  2. 2Cardiovascular and Metabolic Diseases, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany
  3. 3Laboratory of Molecular and Cellular Basis of Embryonic Development, Max-Delbrück Center for Molecular Medicine, Berlin 13125, Germany
  4. 4Department of Neuroscience, Max-Delbrück-Centrum for Molecular Medicine, Berlin 13125, Germany
  5. 5Division of Genetics, Department of Pediatrics, Nemours Children’s Clinic, Jacksonville FL 32207, USA
  6. 6Division of Pediatric Genetics and Metabolism, Department of Pediatrics, University of Minnesota Amplatz Children's Hospital, Minneapolis MN 55454, USA
  7. 7Western Sydney Genetics Program, Royal Alexandra Hospital for Children, Westmead NSW 2145, Australia
  8. 8Institute for Experimental Pediatric Endocrinology, Charité, 13353 Berlin, Germany
  9. 9Division of Inborn Metabolic Diseases, Department of General Pediatrics, University Children’s Hospital, 69120 Heidelberg, Germany
  10. 10Divisions of Metabolism, University Children’s Hospital, 8032 Zürich, Switzerland
  1. *Correspondence to: Klemens Raile MD, E-mail: klemens.raile{at}


Mutations in several genes cause non-autoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1 alpha), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset non-autoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.


  • 11 These authors contributed equally as senior authors

  • Received November 21, 2013.
  • Accepted May 5, 2014.

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