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

  • Am J Hum Genet. 2019 May 2;104(5):985-989. doi: 10.1016/j.ajhg.2019.03.018.
Elisa De Franco  1 ,  Rachel A Watson  2 ,  Wolfgang J Weninger  3 ,  Chi C Wong  2 ,  Sarah E Flanagan  1 ,  Richard Caswell  1 ,  Angela Green  2 ,  Catherine Tudor  2 ,  Christopher J Lelliott  2 ,  Stefan H Geyer  3 ,  Barbara Maurer-Gesek  3 ,  Lukas F Reissig  3 ,  Hana Lango Allen  1 ,  Almuth Caliebe  4 ,  Reiner Siebert  5 ,  Paul Martin Holterhus  6 ,  Asma Deeb  7 ,  Fabrice Prin  8 ,  Robert Hilbrands  9 ,  Harry Heimberg  10 ,  Sian Ellard  1 ,  Andrew T Hattersley  11 ,  Inês Barroso  12
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, Christian-Albrechts-University 24105 Kiel and University Hospital Schleswig-Holstein, 24105 Kiel, Germany; 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; Universitair Ziekenhuis Brussel, 1090 Brussels, Belgium.
  • 10. Vrije Universiteit Brussel, 1090 Brussels, Belgium.
  • 11. Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, UK. Electronic address: [email protected].
  • 12. Wellcome Sanger Institute, CB10 1SA Hinxton, UK. Electronic address: [email protected].
PMID: 31006513 DOI: 10.1016/j.ajhg.2019.03.018
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.

Keywords
agenesis; development; diabetes; genetics; mutation; neonatal; neurological; pancreas.