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  A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3' end processing is associated with intellectual disability in humans

Grozdanov, P. N., Masoumzadeh, E., Kalscheuer, V. M., Bienvenu, T., Billuart, P., Delrue, M.-A., et al. (2020). A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3' end processing is associated with intellectual disability in humans. Nucleic Acids Research (London), 48(17), 9804-9821. doi:10.1093/nar/gkaa689.

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 Creators:
Grozdanov, Petar N. , Author
Masoumzadeh, Elahe , Author
Kalscheuer, Vera M.1, Author              
Bienvenu, Thierry , Author
Billuart, Pierre , Author
Delrue, Marie-Ange , Author
Latham, Michael P. , Author
MacDonald, Clinton C. , Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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 Abstract: CSTF2 encodes an RNA-binding protein that is essential for mRNA cleavage and polyadenylation (C/P). No disease-associated mutations have been described for this gene. Here, we report a mutation in the RNA recognition motif (RRM) of CSTF2 that changes an aspartic acid at position 50 to alanine (p.D50A), resulting in intellectual disability in male patients. In mice, this mutation was sufficient to alter polyadenylation sites in over 1300 genes critical for brain development. Using a reporter gene assay, we demonstrated that C/P efficiency of CSTF2D50A was lower than wild type. To account for this, we determined that p.D50A changed locations of amino acid side chains altering RNA binding sites in the RRM. The changes modified the electrostatic potential of the RRM leading to a greater affinity for RNA. These results highlight the significance of 3' end mRNA processing in expression of genes important for brain plasticity and neuronal development.

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Language(s): eng - English
 Dates: 2020-08-182020-08-202020-09-25
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: DOI: 10.1093/nar/gkaa689
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Title: Nucleic Acids Research (London)
  Other : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: 18 Volume / Issue: 48 (17) Sequence Number: - Start / End Page: 9804 - 9821 Identifier: ISSN: 0305-1048 (print) 1362-4962 (online)
CoNE: https://pure.mpg.de/cone/journals/resource/110992357379342