Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism

Widowati, Esti; Ernst, Sabrina; Hausmann, Ralf; Müller‐Newen, Gerhard; Becker, Walter

doi:10.1242/bio.032862

Cited by 27 publications

(25 citation statements)

References 65 publications

(101 reference statements)

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“…The strikingly similar features of previously reported individuals with MRD7 were intrauterine growth retardation (IUGR), microcephaly, severe intellectual disability, brain abnormalities (MRI), global developmental delay, speech and motor delay, seizures, behavioral issues, feeding difficulties, broad-based gait, and dysmorphic facies (Bronicki et al, 2015; Luco et al, 2016; Widowati et al, 2018). In this report, the patient with the de novo heterozygous mutation of DYRK1A (c.930C > A, p.Tyr310*) displayed typically clinical features, which are closely resembling the syndrome.…”

Section: Discussionsupporting

confidence: 69%

A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

et al. 2019

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Autosomal dominant mental retardation-7 (MRD7) is a rare anomaly, characterized by severe intellectual disability, feeding difficulties, behavior abnormalities, and distinctive facial features, including microcephaly, deep-set eyes, large simple ears, and a pointed or bulbous nasal tip. Some studies show that the disorder has a close correlation with variants in DYRK1A. Herein we described a Chinese girl presenting typical clinical features diagnosed at 4 years old. Whole-exome sequencing of the familial genomic DNA identified a novel mutation c.930C > A (p.Tyr310*) in exon 7 of DYRK1A in the proband. The nonsense mutation was predicted to render the truncation of the protein. Our results suggested that the de novo heterozygous mutation in DYRK1A was responsible for the MRD7 in this Chinese family, which both extended the knowledge of mutation spectrum in MRD7 patients and highlighted the clinical application of exome sequencing.

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Section: Discussionsupporting

confidence: 69%

A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

et al. 2019

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“…According to previous reports, the C-terminal end of the DYRK1A kinase domain is required for protein stability as well as kinase activity [42][43][44] . Thus, loss of this region in the DYRK1A-E396ter mutant may directly affect protein stability.…”

Section: Discussionmentioning

confidence: 94%

A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay

Lee

Choi

Kwon

et al. 2020

Sci Rep

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Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is essential for human development, and DYRK1A haploinsufficiency is associated with a recognizable developmental syndrome and variable clinical features. Here, we present a patient with DYRK1A haploinsufficiency syndrome, including facial dysmorphism, delayed motor development, cardiovascular system defects, and brain atrophy. Exome sequencing identified a novel de novo heterozygous mutation of the human DYRK1A gene (c.1185dup), which generated a translational termination codon and resulted in a C-terminally truncated protein (DYRK1A-E396ter). To study the molecular effect of this truncation, we generated mammalian cell and Drosophila models that recapitulated the DYRK1A protein truncation. Analysis of the structure and deformation energy of the mutant protein predicted a reduction in protein stability. Experimentally, the mutant protein was efficiently degraded by the ubiquitin-dependent proteasome pathway and was barely detectable in mammalian cells. More importantly, the mutant kinase was intrinsically inactive and had little negative impact on the wild-type protein. Similarly, the mutant protein had a minimal effect on Drosophila phenotypes, confirming its loss-of-function in vivo. Together, our results suggest that the novel heterozygous mutation of DYRK1A resulted in loss-offunction of the kinase activity of DYRK1A and may contribute to the developmental delay observed in the patient. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a member of the highly conserved DYRK kinase family that belongs to the CMGC kinase superfamily. DYRK1A phosphorylates serine and threonine residues on its target substrates and autophosphorylates its own tyrosine residues 1,2. Due to the variety of proteins that DYRK1A phosphorylates, it plays essential roles in a wide range of cellular signalling pathways and processes, including neurogenesis, neuronal differentiation and proliferation 3 , synaptic transmission 4 , cell cycle 5 , apoptosis 6 , splicing 7 , and RNA transcription 8. Many of these pathways and processes regulate neurological

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“…No difference between wild type and mutant DYRK1A was observed under these conditions. We have recently found that a pathogenic DYRK1A variant (L295F) with normal content of phosphotyrosine exhibited reduced catalytic activity in kinase assays [ 9 ]. Therefore, we measured the enzymatic activity of DYRK1A-D138P and K150C by immunocomplex kinase assays.…”

Section: Main Textmentioning

confidence: 99%

“…We employed an in vitro-translation system that is reconstituted from recombinant proteins and purified E. coli ribosomes to examine the effect of the DH box mutations in the absence of any chaperones or other proteins that might be involved in DYRK1A maturation. With the help of this approach, we have recently shown impaired tyrosine autophosphorylation of DYRK1A-L295F in vitro, although phosphotyrosine levels were normal in mammalian cells [ 9 ]. For this experiment, we used a DYRK1A deletion (DYRK1A 28–499 ) construct which lacked the C-terminal sequence regions that are subject to truncation in E. coli .…”

Section: Main Textmentioning

confidence: 99%

“…Samples were incubated for 90 min at 37 °C before tyrosine autophosphorylation of the reaction products was assessed by immunoblot analysis a . DYRK1A-L295F was included as a control because this mutation is known to reduce tyrosine autophosphorylation in this assay [ 9 ] For quantification, pY321 signals were normalized to the total amounts of recombinant DYRK1A ( b ) (means and s.d., n = 3). The differences in relative tyrosine autophosphorylation between wild type and mutant were tested for statistical significance by One sample t test (*p < 0.05) …”

Section: Main Textmentioning

confidence: 99%

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Mutational analysis of two residues in the DYRK homology box of the protein kinase DYRK1A

2018

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ObjectiveDual specificity tyrosine phosphorylation-regulated kinases (DYRK) contain a characteristic sequence motif (DYRK homology box, DH box) that is located N-terminal of the catalytic domain and supports the autophosphorylation of a conserved tyrosine during maturation of the catalytic domain. Two missense mutations in the DH box of human DYRK1B were recently identified as causative of a rare familiar form of metabolic syndrome. We have recently shown that these amino acid exchanges impair maturation of the kinase domain. Here we report the characterization of DYRK1A point mutants (D138P, K150C) that correspond to the pathogenic DYRK1B variants (H90P, R102C).ResultsWhen expressed in HeLa cells, DYRK1A-D138P and K150C showed no significant difference from wild type DYRK1A regarding the activating tyrosine autophosphorylation or catalytic activity towards exogenous substrates. However, both DYRK1A variants were underphosphorylated on tyrosine when expressed in a bacterial cell free in vitro translation system. These results suggest that D138 and K150 participate in the maturation of the catalytic domain of DYRK1A albeit the mutation of these residues is compensated under physiological conditions.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3416-4) contains supplementary material, which is available to authorized users.

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Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism

Cited by 27 publications

References 65 publications

A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay

Mutational analysis of two residues in the DYRK homology box of the protein kinase DYRK1A

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