New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome

Park, Joongkyu; Chung, Kwang Chul

doi:10.5607/en.2013.22.4.244

Cited by 58 publications

(54 citation statements)

References 38 publications

(48 reference statements)

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“…Several recent reviews have discussed in detail the numerous targets of Dyrk1a , and have suggested how molecular mechanisms altered by excessive Dyrk1a could affect cognitive and behavioral processes (Wegiel et al. ; Park and Chung ; Duchon and Herault ; Antonarakis ). In addition, several reports have described potential Dyrk1a inhibitors and their possible use for correcting DS‐related deficits (de la Torre and Dierssen ; Becker et al.…”

Section: The Role Of Ds Mouse Models In Finding Therapiesmentioning

confidence: 99%

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

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Section: The Role Of Ds Mouse Models In Finding Therapiesmentioning

confidence: 99%

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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“…When present in three copies, DYRK1A is one of two genes thought to be primarily responsible for neurocognitive deficits associated with Down syndrome. 9, 10 Previously, disruption due to translocation or deletion of DYRK1A was reported in four individuals with intellectual disability (ID), primary microcephaly and overlapping facial dysmorphisms (Supplementary Figure 1) pointing towards a possible emerging syndrome. 11–13 Four individuals with DYRK1A variants have recently been concisely reported.…”

Section: Introductionmentioning

confidence: 99%

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene are thought to play a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7,162 ASD/DD patients (2,446 previously reported) and 2,169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8,696 controls identified a significant enrichment of DYRK1A truncating mutations (p = 0.00851) and an excess of de novo mutations (p = 2.53×10−10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n = 5) and recontacted (n = 3) cases to previous case reports, including larger CNV and translocation events (n = 7), identifies a syndromal disorder among the 15 patients. It is characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia, and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

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“…6,7 Out of the autosomal genes known to have a role in severe ID, the dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK1A) gene (OMIM 600855) has been one of the most extensively studied. [8][9][10][11] Interest in DYRK1A originated because of its genomic localization within the Down syndrome critical region (DSCR) on chromosome 21q22, a chromosomal region that is presumed to be largely responsible for the neuropathologic abnormalities observed in Down syndrome. 12 DYRK1A exhibits an extraordinarily high degree of protein sequence conservation in animals across all vertebrates, 13 and animal models have been instrumental in determining the functions of the encoded proline-directed serine/threonine kinase.…”

Section: Introductionmentioning

confidence: 99%

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

et al. 2015

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The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

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New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome

Cited by 58 publications

References 38 publications

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

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