title: A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay.
abstract: Recently, GATA6 heterozygous loss-of-function mutations were reported to cause pancreatic agenesis and congenital heart defects (PACHD [OMIM:600001]). However, the molecular mechanisms resulting from premature termination codons have not been examined in this disorder. The objective of this study was to perform a genetic analysis of a patient with PACHD. A female patient presented with ventricular septal defect, patent ductus arteriosus, and congenital diaphragmatic hernia at birth. Permanent neonatal diabetes mellitus and pancreatic exocrine deficiency due to pancreatic agenesis was diagnosed at 1 month of age. PCR-direct sequencing of GATA6 revealed that the patient is heterozygous for a novel de novo nonsense mutation of c.1477C>T, p. Arg493X in exon 5. RT-PCR direct sequencing of the RT-PCR products of total RNA from peripheral blood of the patient for the region encompassing exons 4-6 revealed only the wild-type allele. This finding provides the evidence for the occurrence of nonsense-mediated mRNA decay (NMD) in the p.Arg493X mutation. Quantitative RT-PCR analysis revealed that the expression of GATA6 transcript in the patient was less than half compared with normal control samples. This is the first evidence that GATA6 haploinsufficiency is caused by NMD in vivo, and we conclude that GATA6 haploinsufficiency causes not only PACHD but may affect other organs derived from the endoderm. Further screenings of GATA6 mutations in patients with various forms of diabetes and/or congenital heart disease with other visceral malformation may reveal the impact of GATA6 mutations on diabetes and congenital malformation.
authors: Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan.
authors: Shigeru
authors: S
authors: Suzuki
authors: Atsushi
authors: A
authors: Nakao
authors: Ashoor R
authors: AR
authors: Sarhat
authors: Akiko
authors: A
authors: Furuya
authors: Kumihiro
authors: K
authors: Matsuo
authors: Yusuke
authors: Y
authors: Tanahashi
authors: Hiroki
authors: H
authors: Kajino
authors: Hiroshi
authors: H
authors: Azuma
mesh_terms: D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D003920:Diabetes Mellitus / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics*; D015870:Gene Expression; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D010179:Pancreas / Q000002:abnormalities*; D012333:RNA, Messenger / Q000235:genetics; D014057:Tomography, X-Ray Computed
chemical_list: D018389:Codon, Nonsense; D050993:GATA6 Transcription Factor; D012333:RNA, Messenger
keywords: GATA6; congenital heart defect; neonatal diabetes mellitus; pancreatic agenesis