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Haploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A. Four of the substitutions eliminated tyrosine autophosphorylation (L245R, F308V, S311F, S346P), indicating that these variants lacked kinase activity. Tyrosine phosphorylation of DYRK1A-L295F in mammalian cells was comparable to wild type, although the mutant showed lower catalytic activity and reduced thermodynamic stability in cellular thermal shift assays. In addition, we observed that one variant (DYRK1A-T588N) with a mutation outside the catalytic domain did not differ from wild-type DYRK1A in tyrosine autophosphorylation, catalytic activity or subcellular localization. These results suggest that the pathogenic missense variants in the catalytic domain of DYRK1A impair enzymatic function by affecting catalytic residues or by compromising the structural integrity of the kinase domain.This article has an associated First Person interview with the first author of the paper.
Pubmed ID: 29700199
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A commercial antibody supplier and provider of various services.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 9, 2023. An aggregated data platform for genome sequencing data created by a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community. The data set provided on this website spans 61,486 unrelated individuals sequenced as part of various disease-specific and population genetic studies. They have removed individuals affected by severe pediatric disease, so this data set should serve as a useful reference set of allele frequencies for severe disease studies. All of the raw data from these projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects. They ask that you not publish global (genome-wide) analyses of these data until after the ExAC flagship paper has been published, estimated to be in early 2015. If you''re uncertain which category your analyses fall into, please email them. The aggregation and release of summary data from the exomes collected by the Exome Aggregation Consortium has been approved by the Partners IRB (protocol 2013P001477, Genomic approaches to gene discovery in rare neuromuscular diseases).
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line COS-7 is a Transformed cell line with a species of origin Chlorocebus aethiops (Green monkey)
View all literature mentionsThis unknown targets GFP Antibody
View all literature mentionsThis unknown targets Phospho-HIPK2 (Tyr361)
View all literature mentionsUser interface software for Carl Zeiss light microscopy imaging systems. ZEN is the universal user interface you will see on every imaging system from ZEISS. After selecting fluorophore, ZEN applies the necessary settings to collect and organize data.
View all literature mentionsSoftware for molecular visualization and modeling. It provides fast OpenGL-based visualization of molecular structures, molecular mechanics methods (minimization, MD simulation using the AMBER, CHARMM, and MMFF94 force fields), calculation and visualization of electrostatic properties (FDPB) and molecular editing features.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
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