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A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2014 Feb; Vol. 164A (2), pp. 476-9. Date of Electronic Publication: 2013 Dec 05. - Publication Year :
- 2014
-
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.<br /> (© 2013 Wiley Periodicals, Inc.)
- Subjects :
- Child, Preschool
DNA Mutational Analysis
Exons
Female
Gene Expression
Haploinsufficiency
Heterozygote
Humans
Nonsense Mediated mRNA Decay
RNA, Messenger genetics
Tomography, X-Ray Computed
Codon, Nonsense
Diabetes Mellitus diagnosis
Diabetes Mellitus genetics
GATA6 Transcription Factor genetics
Heart Defects, Congenital diagnosis
Heart Defects, Congenital genetics
Pancreas abnormalities
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 164A
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 24310933
- Full Text :
- https://doi.org/10.1002/ajmg.a.36275