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Lookup NU author(s): Dr Marta Bertoli, Dr Anne Lampe, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author 2016. Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.
Author(s): Evers JM, Laskowski RA, Bertolli M, Clayton-Smith J, Deshpande C, Eason J, Elmslie F, Flinter F, Gardiner C, Hurst JA, Kingston H, Kini U, Lampe AK, Lim D, Male A, Naik S, Parker MJ, Price S, Robert L, Sarkar A, Straub V, Woods G, Thornton JM, The DDD Study, Wright CF
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2017
Volume: 26
Issue: 3
Pages: 519-526
Print publication date: 01/02/2017
Online publication date: 04/01/2017
Acceptance date: 24/11/2016
Date deposited: 26/05/2017
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: https://doi.org/10.1093/hmg/ddw409
DOI: 10.1093/hmg/ddw409
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