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Hum Mol Genet. 2017 Feb 1;26(3):519-526. doi: 10.1093/hmg/ddw409.

Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.

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European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
Manchester Centre for Genomic Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, USA.
Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK.
Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK.
South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, St George's, University of London, Cranmer Terrace, London, UK.
West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute Of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London, UK.
Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, The Churchill Old Road, Oxford, UK.
South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK.
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK.
East Anglian Medical Genetics Service, Box 134, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK and.
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.


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.

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