GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes
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KeywordsCongenital heart disease GATA6 Neonatal diabetes mellitus Pancreatic agenesis Whole-exome sequencing
GATA-binding protein 6
Neonatal diabetes mellitus
To the Editor: Pancreatic agenesis is an extremely rare cause of permanent neonatal diabetes mellitus (NDM) in humans. It can be associated with severe intrauterine growth retardation as well as a plethora of abnormalities or malformations in the heart, biliary tract, gut, thyroid or brain [1, 2, 3]. To date, mutations in three genes have been shown to cause pancreatic agenesis, namely, PDX1 , PTF1A , and most recently GATA6 , all three of which encode transcription factors. The GATA6 study reported heterozygous coding mutations in a dozen individuals with permanent NDM presumed to be due to pancreatic agenesis . The genetic evidence supporting the pathogenicity of these mutations seemed quite strong as the reported mutations had arisen de novo and none of these mutations was present in the 1,000 Genome Project database . The authors concluded that GATA6 may have a key role in human pancreatic development, with strong implications for beta cell regenerative medicine in diabetes . In the present study, we aimed to qualify this conclusion by reporting a case study of a non-consanguineous family.
Clinical data of the three carriers of the GATA6 p.Lys502Aspfs*5 mutation
x (permanent NDM)
x (onset at 13 years)
x (requiring surgery)
x (requiring surgery)
Gall bladder agenesis
Intra-uterine growth retardation
p.Lys502Aspfs*5 heterozygous mutation
Based on these findings, we needed to question the proposed key role of GATA6 in pancreatic beta cell development using public and in-house expression databases. First, according to public databases, GATA6 expression is unambiguously weak in human whole pancreas (Gene Portal System, http://biogps.org/, last accessed March 2012). In our experiments on isolated human pancreatic islets and beta cells (ESM Methods), this was also the case (ESM Fig. 2a). In a rat model of pancreatic endocrine cell differentiation and proliferation (ESM Methods), Gata6 expression is constantly weak from precursor cells to mature beta cells (ESM Fig. 2b). Moreover, between embryonic days E13.5 and E17, there is no significant change in Gata6 expression in pancreatic epithelium (ESM Fig. 2c). GATA6 expression is also not significantly different between pancreatic epithelium and mesenchyme in rat and human samples, at embryonic day E12 and at ~7–11 weeks of development, respectively (ESM Methods, ESM Fig. 2d, e). Therefore, our results do not suggest a key role of GATA6 in the specific beta cell lineage, but these results would need further investigation as they are limited to gene expression analyses. In mice, in which GATA6 has been further studied, expression-based analyses suggest that GATA6 could play a role in very early pancreas specification [6, 7, 8]. Nevertheless, it has been reported that transgenic mouse embryos expressing a GATA6–engrailed dominant repressor fusion protein in the pancreatic epithelium and in islets revealed two distinct phenotypes, either pancreatic agenesis or a simple reduction in pancreatic tissue , implying a putative spectrum of phenotypes, as we noted in our family. Therefore, the role of GATA6 in pancreatic morphogenesis is very variable, which could be due to various epigenetic effects or partial replacement of GATA6 by other transcription factors from the GATA family that are expressed in the pancreas (e.g. GATA4).
Taken together, our results and other genetic studies indicate GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes. We suggest that in carriers of a GATA6-inactivating mutation, diabetes (when present) is due to a severe multi-tissue developmental defect rather than a specific impairment of beta cell lineage. The present study is limited by a lack of functional analyses of our identified frameshift mutation. Nevertheless, a de novo deletion which leads to a premature termination codon at the 514th amino acid has previously been reported in an NDM patient with pancreatic agenesis . Our deletion, which leads to a termination codon at the 507th amino acid, is likely to have a functional effect similar to that reported by Allen et al .
We are sincerely indebted to the family for participation in the study. We thank P. Gallina (CNRS UMR8199 unit, Lille, France) for clinical data capture. We also thank our collaborators in the French study of neonatal diabetes: K. Busiah (Necker Hospital, Paris, France), H. Cavé (Robert Debré Hospital, Paris, France) and A. Simon (Necker Hospital, Paris, France).
Our study was supported by the transnational European research grant on Rare Diseases (ERANET-09-RARE-005) and by the French Agence Nationale de la Recherche (ANR-10-LABX-46 and ANR-10-EQPX-07-01).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
AB and PF designed the study, interpreted the data and wrote the manuscript; MV, BG, MP and PC analysed the clinical data and revised the manuscript; LR, JK-C, FP and RS contributed to acquisition of gene expression data (in rat and/or in human) and revised the manuscript; OS and FD performed the bioinformatic analyses and revised the manuscript; ED and MH performed the sequencing and revised the manuscript; PF is the guarantor of the manuscript. All authors of the paper have read and approved the final version submitted.