Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders
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 Development...
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Published in | Human molecular genetics Vol. 26; no. 3; pp. 519 - 526 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Oxford University Press
01.02.2017
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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. |
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AbstractList | 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. 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 | Price, Sue Thornton, Janet M Kini, Usha Naik, Swati Sarkar, Ajoy Parker, Michael J Hurst, Jane A Kingston, Helen Eason, Jacqueline Lim, Derek Clayton-Smith, Jill Lampe, Anne K Male, Alison Straub, Volker Evers, Jochem M G Gardiner, Carol Laskowski, Roman A Robert, Leema Bertolli, Marta Deshpande, Charu Flinter, Frances Wright, Caroline F Elmslie, Frances Woods, Geoff |
AuthorAffiliation | 10 South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK 11 West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham Women’s Hospital, Edgbaston, Birmingham, UK 8 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London, UK 1 European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK 5 Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK 2 Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK 7 West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute Of Medical Genetics, Yorkhill Hospital, Glasgow, UK 9 Department of Clinical Genetics, Oxf |
AuthorAffiliation_xml | – name: 4 Clinical Genetics Department, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, Great Maze Pond, London, UK – name: 3 Manchester Centre for Genomic Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, USA – name: 11 West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham Women’s Hospital, Edgbaston, Birmingham, UK – name: 13 East Anglian Medical Genetics Service, Box 134, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK and – name: 9 Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, The Churchill Old Road, Oxford, UK – name: 1 European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK – name: 8 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London, UK – name: 7 West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute Of Medical Genetics, Yorkhill Hospital, Glasgow, UK – name: 14 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK – name: 6 South West Thames Regional Genetics Centre, St George’s Healthcare NHS Trust, St George’s, University of London, Cranmer Terrace, London, UK – name: 2 Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK – name: 5 Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK – name: 10 South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK – name: 12 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK |
Author_xml | – sequence: 1 givenname: Jochem M G surname: Evers fullname: Evers, Jochem M G organization: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK – sequence: 2 givenname: Roman A surname: Laskowski fullname: Laskowski, Roman A organization: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK – sequence: 3 givenname: Marta surname: Bertolli fullname: Bertolli, Marta organization: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK – sequence: 4 givenname: Jill surname: Clayton-Smith fullname: Clayton-Smith, Jill organization: Manchester Centre for Genomic Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, USA – sequence: 5 givenname: Charu surname: Deshpande fullname: Deshpande, Charu organization: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK – sequence: 6 givenname: Jacqueline surname: Eason fullname: Eason, Jacqueline organization: Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK – sequence: 7 givenname: Frances surname: Elmslie fullname: Elmslie, Frances organization: South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, St George's, University of London, Cranmer Terrace, London, UK – sequence: 8 givenname: Frances surname: Flinter fullname: Flinter, Frances organization: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK – sequence: 9 givenname: Carol surname: Gardiner fullname: Gardiner, Carol organization: West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute 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Foundation Trust, The Churchill Old Road, Oxford, UK – sequence: 19 givenname: Leema surname: Robert fullname: Robert, Leema organization: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK – sequence: 20 givenname: Ajoy surname: Sarkar fullname: Sarkar, Ajoy organization: Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, UK – sequence: 21 givenname: Volker surname: Straub fullname: Straub, Volker organization: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK – sequence: 22 givenname: Geoff surname: Woods fullname: Woods, Geoff organization: East Anglian Medical Genetics Service, Box 134, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK and – sequence: 23 givenname: Janet M surname: Thornton fullname: Thornton, Janet M organization: European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK – sequence: 24 givenname: Caroline F surname: Wright fullname: Wright, Caroline F organization: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK |
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Snippet | Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is... Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is... |
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SubjectTerms | Autistic Disorder - genetics Autistic Disorder - pathology Developmental Disabilities - genetics Developmental Disabilities - physiopathology Dyrk Kinases Female Haploinsufficiency - genetics Humans Intellectual Disability - genetics Intellectual Disability - pathology Male Mutation Mutation, Missense Pedigree Phenotype Protein Conformation Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - genetics Protein-Tyrosine Kinases - chemistry Protein-Tyrosine Kinases - genetics Structure-Activity Relationship |
Title | Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders |
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