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Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2017 Feb 01; Vol. 26 (3), pp. 519-526. - Publication Year :
- 2017
-
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.<br /> (© The Author 2017. Published by Oxford University Press.)
- Subjects :
- Autistic Disorder pathology
Developmental Disabilities physiopathology
Female
Haploinsufficiency genetics
Humans
Intellectual Disability pathology
Male
Mutation
Mutation, Missense
Pedigree
Phenotype
Protein Conformation
Protein Serine-Threonine Kinases chemistry
Protein-Tyrosine Kinases chemistry
Structure-Activity Relationship
Dyrk Kinases
Autistic Disorder genetics
Developmental Disabilities genetics
Intellectual Disability genetics
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28053047
- Full Text :
- https://doi.org/10.1093/hmg/ddw409