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

Elisa De Franco; Rachel A Watson; Wolfgang J Weninger; Chi C Wong; Sarah E Flanagan; Richard Caswell; Angela Green; Catherine Tudor; Christopher J Lelliott; Stefan H Geyer; Barbara Maurer-Gesek; Lukas F Reissig; Hana Lango Allen; Almuth Caliebe; Reiner Siebert; Paul Martin Holterhus; Asma Deeb; Fabrice Prin; Robert Hilbrands; Harry Heimberg; Sian Ellard; Andrew T Hattersley; Inês Barroso

doi:10.1016/j.ajhg.2019.03.018

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. Epub 2019 Apr 18.

Authors

Elisa De Franco¹, Rachel A Watson², Wolfgang J Weninger³, Chi C Wong², Sarah E Flanagan¹, Richard Caswell¹, Angela Green², Catherine Tudor², Christopher J Lelliott², Stefan H Geyer³, Barbara Maurer-Gesek³, Lukas F Reissig³, Hana Lango Allen¹, Almuth Caliebe⁴, Reiner Siebert⁵, Paul Martin Holterhus⁶, Asma Deeb⁷, Fabrice Prin⁸, Robert Hilbrands⁹, Harry Heimberg¹⁰, Sian Ellard¹, Andrew T Hattersley¹¹, Inês Barroso¹²

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].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Developmental Disabilities / etiology*
Developmental Disabilities / pathology
Embryo, Mammalian / metabolism
Embryo, Mammalian / pathology
Female
Holoprosencephaly / etiology*
Holoprosencephaly / pathology
Humans
Infant
Infant, Newborn
Infant, Newborn, Diseases / etiology*
Infant, Newborn, Diseases / pathology
Male
Mice
Mice, Knockout
Mutation*
Nervous System Diseases / etiology*
Nervous System Diseases / pathology
Pancreas / abnormalities*
Pancreas / pathology
Pancreatic Diseases / congenital*
Pancreatic Diseases / etiology
Pancreatic Diseases / pathology
Pedigree
Phenotype
Sequence Homology
Syndrome
Transcription Factors / genetics*

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

Authors

Affiliations

Abstract

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