title: Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations.
abstract: Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high-throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development. Here we present the clinical history, evaluation, and the genetic and molecular analysis from two patients with pancreatic agenesis. Both patients were born with intrauterine growth restriction, minor heart defects and neonatal diabetes. In both cases, pancreatic agenesis was confirmed by imaging studies. The patients are clinically stable with pancreatic enzymes and insulin therapy. In order identify the etiology for their disease, we performed whole exome sequencing on both patients. For each proband we identified a de novo heterozygous mutation in the GATA6 gene. GATA6 is a homeobox containing transcription factor involved in both early development of the pancreas and heart. In vitro functional analysis of one of the variants revealed that the mutation creates a premature stop codon in the coding sequence resulting in the production of a truncated protein with loss of activity. These results show how genetic mutations in GATA6 may lead to functional inactivity and pancreatic agenesis in humans.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Chao
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Kristen D
authors.initials: KD
authors.lastname: McKnight
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Cox
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States of America; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States of America; Program in Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Feldman
mesh_terms: D050993:GATA6 Transcription Factor / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010179:Pancreas / Q000002:abnormalities*; D010182:Pancreatic Diseases / Q000151:congenital* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human