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      A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development

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          Abstract

          We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

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          GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo.

          E. Morrisey, Z. Tang, K. Sigrist … (1998)
          GATA6 belongs to a family of zinc finger transcription factors that play important roles in transducing nuclear events that regulate cellular differentiation and embryonic morphogenesis in vertebrate species. To examine the function of GATA6 during embryonic development, gene targeting was used to generate GATA6-deficient (GATA6(-/-)) ES cells and mice harboring a null mutation in GATA6. Differentiated embryoid bodies derived from GATA6(-/-) ES cells lack a covering layer of visceral endoderm and severely attenuate, or fail to express, genes encoding early and late endodermal markers, including HNF4, GATA4, alpha-fetoprotein (AFP), and HNF3beta. Homozygous GATA6(-/-) mice died between embryonic day (E) 6.5 and E7. 5 and exhibited a specific defect in endoderm differentiation including severely down-regulated expression of GATA4 and absence of HNF4 gene expression. Moreover, widespread programmed cell death was observed within the embryonic ectoderm of GATA6-deficient embryos, a finding also observed in HNF4-deficient embryos. Consistent with these data, forced expression of GATA6 activated the HNF4 promoter in nonendodermal cells. Finally, to examine the function of GATA6 during later embryonic development, GATA6(-/-)-C57BL/6 chimeric mice were generated. lacZ-tagged GATA6(-/-) ES cells contributed to all embryonic tissues with the exception of the endodermally derived bronchial epithelium. Taken together, these data suggest a model in which GATA6 lies upstream of HNF4 in a transcriptional cascade that regulates differentiation of the visceral endoderm. In addition, these data demonstrate that GATA6 is required for establishment of the endodermally derived bronchial epithelium.
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            Development of the Human Pancreas From Foregut to Endocrine Commitment

            Rachel Jennings, Andrew Berry, Rebecca Kirkwood-Wilson … (2013)
            Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation toward a β-cell fate. However, almost no information exists on the early events of human pancreatic specification in the distal foregut, bud formation, and early development. Here, we have studied the expression profiles of key lineage-specific markers to understand differentiation and morphogenetic events during human pancreas development. The notochord was adjacent to the dorsal foregut endoderm during the fourth week of development before pancreatic duodenal homeobox-1 detection. In contrast to the published data from mouse embryos, during human pancreas development, we detected only a single-phase of Neurogenin 3 (NEUROG3) expression and endocrine differentiation from approximately 8 weeks, before which Nirenberg and Kim homeobox 2.2 (NKX2.2) was not observed in the pancreatic progenitor cell population. In addition to revealing a number of disparities in timing between human and mouse development, these data, directly assembled from human tissue, allow combinations of transcription factors to define sequential stages and differentiating pancreatic cell types. The data are anticipated to provide a useful reference point for stem cell researchers looking to differentiate human PSCs in vitro toward the pancreatic β-cell so as to model human development or enable drug discovery and potential cell therapy.
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              GATA6 haploinsufficiency causes pancreatic agenesis in humans.

              Charles Shaw, Sarah Flanagan, Sian Ellard … (2011)
              Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.
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                Author and article information

                Contributors
                Andrew T. Hattersley
                Inês Barroso
                Journal
                Journal ID (nlm-ta): Am J Hum Genet
                Journal ID (iso-abbrev): Am. J. Hum. Genet
                Title: American Journal of Human Genetics
                Publisher: Elsevier
                ISSN (Print): 0002-9297
                ISSN (Electronic): 1537-6605
                Publication date PMC-release: 18 April 2019
                Publication date (Print): 02 May 2019
                Publication date (Electronic): 18 April 2019
                Volume: 104
                Issue: 5
                Pages: 985-989
                Affiliations
                [1 ]Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, UK
                [2 ]Wellcome Sanger Institute, CB10 1SA Hinxton, UK
                [3 ]Centre for Anatomy and Cell Biology & MIC, Medical University of Vienna, 1090 Vienna, Austria
                [4 ]Institute of Human Genetics, Christian-Albrechts-University 24105 Kiel and University Hospital Schleswig-Holstein, 24105 Kiel, Germany
                [5 ]Institute of Human Genetics, Ulm University & Ulm University Medical Center, 89081 Ulm, Germany
                [6 ]Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University 24105 Kiel and University Hospital Schleswig-Holstein, 24105 Kiel, Germany
                [7 ]Paediatric Endocrinology Department, Mafraq Hospital, 2951 Abu Dhabi, United Arab Emirates
                [8 ]The Francis Crick Institute, NW1 1ST London, UK
                [9 ]Vrije Universiteit Brussel, 1090 Brussels, Belgium
                [10 ]Universitair Ziekenhuis Brussel, 1090 Brussels, Belgium
                Author notes
                [∗ ]Corresponding author a.t.hattersley@ 123456exeter.ac.uk
                [∗∗ ]Corresponding author ines.barroso@ 123456mrc-epid.cam.ac.uk
                [11]

                These authors contributed equally to this work

                [12]

                These authors contributed equally to this work

                [13]

                Present address: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, CB2 0SL Cambridge, UK

                Article
                Publisher ID: S0002-9297(19)30114-4
                DOI: 10.1016/j.ajhg.2019.03.018
                PMC ID: 6506862
                PubMed ID: 31006513
                SO-VID: 5e62835c-12f7-4cb7-811c-b73e314e8f78
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 3 December 2018
                Date accepted : 18 March 2019
                Categories
                Subject: Report

                ScienceOpen disciplines: Genetics
                Keywords: neonatal,diabetes,pancreas,agenesis,genetics,mutation,development,neurological
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: neonatal, diabetes, pancreas, agenesis, genetics, mutation, development, neurological

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