Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome wide SNP typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All 4 cases were diagnosed with diabetes at birth and are insulin treated. Two of the 4 had exocrine pancreatic insufficiency requiring replacement but none of the affected individuals have neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts on the severity of clinical features found in patients.The authors thank the families for participating in this study. We are grateful to Annet Damhuis and Anna-Maria Bussell and the Research Center, College of Medicine, King Saud University for their technical assistance and to Ward Coats for helpful discussions regarding PTF1A structure. ATH and SE are the recipients of a Wellcome Trust Senior Investigator award and this funded the genetic/clinical part of this study (WT 098395). ATH is employed as a core member of staff within the NIHR funded Exeter Clinical Research Facility and is a NIHR senior investigator. GHS and RJM were supported by NIH grant R01-DK061220