Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis

  • Nat Genet. 2014 Jan;46(1):61-64. doi: 10.1038/ng.2826.
Michael N Weedon  #  1 ,  Ines Cebola  #  2  3 ,  Ann-Marie Patch  #  1 ,  Sarah E Flanagan  1 ,  Elisa De Franco  1 ,  Richard Caswell  1 ,  Santiago A Rodríguez-Seguí  2  3  4 ,  Charles Shaw-Smith  1 ,  Candy H-H Cho  5 ,  Hana Lango Allen  1 ,  Jayne Al Houghton  1 ,  Christian L Roth  6 ,  Rongrong Chen  7 ,  Khalid Hussain  8  9 ,  Phil Marsh  10 ,  Ludovic Vallier  5 ,  Anna Murray  1 ,  International Pancreatic Agenesis Consortium ,  Sian Ellard  #  1 ,  Jorge Ferrer  #  2  3  11 ,  Andrew T Hattersley  #  1
Affiliations
  • 1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
  • 2. Genomic Regulation of Pancreatic Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Spain.
  • 3. CIBER de Diabetes y Enfermedades Metabólicas, 08036 Barcelona, Spain.
  • 4. Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE)-Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina.
  • 5. Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, West Forvie Site, Robinson Way, Cambridge, UK.
  • 6. Seattle Children's Hospital Research Institute, Seattle, WA 98101, USA.
  • 7. School of Biomedical Science, Waterloo Campus, King's College London, London, UK.
  • 8. London Centre for Paediatric Endocrinology and Metabolism, in partnership with the Great Ormond Street Hospital for Children National Health Service Trust, London, UK.
  • 9. Institute of Child Health, University College London, London, UK.
  • 10. Diabetes Research Group, Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK.
  • 11. Department of Medicine, Imperial College, London, UK.
  • # Contributed equally.
PMID: 24212882 DOI: 10.1038/ng.2826
Abstract

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome Sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome Sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.