Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis

WEEDON, M.N.; CEBOLA, I.; PATCH, A.M.; FLANAGAN, S.; DE FRANCO, E.; CASWELL, R.; RODRÍGUEZ SEGUÍ, S.A.; SHAW-SMITH, C.; CHO, C.; ALLEN, H.L.; HOUGHTON, J.; ROTH, C.L.; CHEN, R.; HUSSAIN, K.; MARSH, P.; VALLIER, L.; MURRAY, A.; INTERNATIONAL PANCREATIC AGENESIS CONSORTIUM; ELLARD, S.; FERRER, J.; HATTERSLEY, A.T.

NATURE GENETICS

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2014 vol. 46 p. 61 - 64

1061-4036

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 1 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.