title: Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.
abstract: 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.
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Jochem M G
authors.initials: JM
authors.lastname: Evers
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Laskowski
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Bertolli
authors.affiliation: Manchester Centre for Genomic Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eason
authors.affiliation: South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, St George's, University of London, Cranmer Terrace, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Elmslie
authors.affiliation: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute Of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Gardiner
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: Manchester Centre for Genomic Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, The Churchill Old Road, Oxford, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.affiliation: South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Lampe
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Lim
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Male
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
authors.forename: Swati
authors.initials: S
authors.lastname: Naik
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, The Churchill Old Road, Oxford, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Price
authors.affiliation: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK.
authors.forename: Leema
authors.initials: L
authors.lastname: Robert
authors.affiliation: Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.affiliation: East Anglian Medical Genetics Service, Box 134, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK and.
authors.forename: Geoff
authors.initials: G
authors.lastname: Woods
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Wright
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases