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Nat Genet. 2014 Jan;46(1):61-64. doi: 10.1038/ng.2826. Epub 2013 Nov 10.

Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.

Author information

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

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.

PMID:
24212882
PMCID:
PMC4131753
DOI:
10.1038/ng.2826
[Indexed for MEDLINE]
Free PMC Article
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