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 Chun Wong; Sarah Elizabeth Flanagan; Richard C. Caswell; Angela Green; Catherine L. 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 Tym Hattersley; Inês Barroso

doi:10.1016/j.ajhg.2019.03.018

Key Points

To identify the underlying genetic cause of a novel developmental syndrome characterized by pancreatic agenesis and abnormal forebrain development.
Analyzed clinical and genetic data from three individuals presenting with pancreatic agenesis and abnormal forebrain development.
Investigated the functional impact of the identified variant using a corresponding mouse model.
Identified a recurrent de novo missense mutation in CNOT1 (GenBank: NM_016284.4; c.1603C>T, p.Arg535Cys) in all three affected individuals.
Observed a matching phenotype of impaired pancreatic and neurological development in mice harboring the mutation.

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Implication

Reveals a recurrent de novo CNOT1 missense mutation causing pancreatic agenesis and holoprosencephaly in humans and mice, indicating an essential role for CNOT1 in pancreatic and brain development.

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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Cite This Study

Franco et al. (2019) studied this question.

synapsesocial.com/papers/6ab492654fbe54468a75bd40 https://doi.org/10.1016/j.ajhg.2019.03.018

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

Key Points

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Implication

Abstract

Discussion

Cite This Study

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

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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