Skip to content
Frontiers
Search

Mini Review

Frontiers in Cell and Developmental Biology ·

Volume 14 - 2026 | https://doi.org/10.3389/fcell.2026.1963992

DYRK1A – a gene dose paradox

  • Ante Plećaš1*corresponding author
  • Gillian Gough2
  • Sandra Kunštek3
  • Mirna Babić4
  • Aoife Murray5
  • Dean Nižetić6*corresponding author
  • Ivan Alić1,6*corresponding author
  1. 1Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
  2. 2Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  3. 3Department of Pathophysiology, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
  4. 4Varaždin General Hospital, Varaždin, Croatia
  5. 5ARUK-UCL Drug Discovery Institute, Faculty of Brain Sciences, University College London, London, United Kingdom
  6. 6Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
Article metrics0 viewsView details
PDFCiteMetrics

Abstract

The DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) gene is located on human chromosome 21 (HSA21) within the Down Syndrome Critical Region (DSCR). As a protein kinase, DYRK1A is involved in the regulation of the cell cycle, cell growth, transcription, and cellular communication. It also plays essential roles in embryonic and neuronal development, and in disease pathogenesis. Dysregulation of DYRK1A has been associated with several human disorders, including DYRK1A syndrome, caused by DYRK1A haploinsufficiency (i.e., one functional copy of the gene) and Down syndrome (DS), caused by trisomy 21 (i.e., three functional copies of the gene). DYRK1A is an extremely dosage-sensitive gene and is considered one of the “Goldilocks” genes, for which both increased and decreased gene dosage can lead to pathological phenotypes. Interestingly, these two syndromes share several overlapping clinical features. This apparent paradox represents/highlights a major gap in our current understanding of DYRK1A function and raises important biological questions. In this review, we summarise the most important findings related to both DYRK1A syndrome and Down syndrome, as well as the available human cellular and animal models that provide valuable platforms for future research. To obtain a comprehensive understanding of DYRK1A role, it is necessary to integrate data from multiple experimental systems and sources. Such an integrated approach will facilitate the identification of novel therapeutic targets and support the development of treatments that may ultimately advance to clinical trials.

Keywords

1 Introduction

For physiological development from the zygote to the adult organism, an euploid chromosome complement with a species-specific number of genes precisely located on those chromosomes is essential. However, alterations in gene or chromosome copy number may lead to haploinsufficiency, gene overdosage, or chromosomal aneuploidies such as trisomy. Although most of these abnormalities are lethal and lead to early embryonic death, often before placentation, some are compatible with survival depending on the affected gene or chromosome. The resulting phenotypes vary according to the affected genetic region and the extent of gene dosage imbalance. In this review, we summarise the role of the DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) gene, one of the best-characterised examples of a dosage-sensitive gene which is located on human chromosome 21 (HSA21) within the Down Syndrome Critical Region (DSCR), and discuss its contribution to the pathogenesis of both, DYRK1A syndrome and Down syndrome (DS) (Figure 1). DYRK1A belongs to the CMGC family of protein kinases and primarily regulates cell-cycle progression, cell growth, transcription, and intracellular communication (Varjosalo et al., 2013; Atas-Ozcan et al., 2021; Hammond et al., 2026). In addition, DYRK1A plays essential roles in embryonic development (Johnson et al., 2025), neuronal development including neural progenitor proliferation, neuronal differentiation, dendritic growth, synaptogenesis and brain maturation (Yabut et al., 2010; Tejedor and Hämmerle, 2011; Bellmaine et al., 2017; Pijuan et al., 2022; Cisternas et al., 2025; Courraud et al., 2025) and the pathogenesis of multiple diseases (Guedj et al., 2012; Courraud et al., 2021).

Schematic overview of *DYRK1A* dosage. The *DYRK1A* (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) gene is located on human chromosome 21 (HSA21) within the Down Syndrome Critical Region (DSCR) (left column). Haploinsufficiency of *DYRK1A* causes DYRK1A syndrome, whereas trisomy of HSA21 causes Down syndrome (DS). Despite their opposite genetic mechanisms, these two syndromes share several clinical features, highlighted in the orange box (middle column). The right column summarizes the roles of *DYRK1A* in DNA damage response, Cell Cycle Arrest, Neurogenesis, Retinal Alterations and Alzheimer’s disease. The icons in the figure were created with Adobe Illustrator’s generative object prompt. No generative AI was used to generate Figure 1.
Figure 1. Schematic overview of DYRK1A dosage. The DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) gene is located on human chromosome 21 (HSA21) within the Down Syndrome Critical Region (DSCR) (left column). Haploinsufficiency of DYRK1A causes DYRK1A syndrome, whereas trisomy of HSA21 causes Down syndrome (DS). Despite their opposite genetic mechanisms, these two syndromes share several clinical features, highlighted in the orange box (middle column). The right column summarizes the roles of DYRK1A in DNA damage response, Cell Cycle Arrest, Neurogenesis, Retinal Alterations and Alzheimer’s disease. The icons in the figure were created with Adobe Illustrator’s generative object prompt. No generative AI was used to generate Figure 1.

2 DYRK1A syndrome

DYRK1A syndrome is a rare neurodevelopmental disorder caused by a microdeletion involving DYRK1A (21q22.13), resulting in DYRK1A haploinsufficiency firstly described less than 20 years ago (Møller et al., 2008; Van Bon et al., 2011). It is characterised by a broad spectrum of clinical features, including congenital microcephaly, moderate to severe intellectual disability, developmental delay, profound speech impairment, short stature, distinctive facial features, behavioural abnormalities including autism spectrum disorder (Kurtz-Nelson et al., 2023), anxiety, stereotypic behaviour and impaired social communication (Ji et al., 2015; Luco et al., 2016; Meissner et al., 2020; Courraud et al., 2021; Pijuan et al., 2022; Glass et al., 2026). Interestingly, despite being caused by DYRK1A haploinsufficiency (i.e., loss of one functional copy of DYRK1A) DYRK1A syndrome shares several clinical features with Down syndrome (Antonarakis et al., 2020) which is associated with an extra copy of DYRK1A due to trisomy 21 (T21) (Figure 1).

DYRK1A syndrome is characterised by intellectual disability, developmental delay, autism spectrum disorder, and seizures. Most of these features are also common in Down syndrome, though the mechanisms may be different. This apparent paradox highlights the importance of precise regulation of DYRK1A expression throughout neurodevelopment. Some features are distinctly different, for example, the facial dysmorphism has a different appearance, and microcephaly is not a prominent feature in DS. DYRK1A syndrome has also been recorded to clinically mimic other neurodevelopmental conditions, such as Cockayne syndrome (Le May et al., 2025).

Depending on the nature of the causative mutation, the molecular consequences range from loss of protein stability, complete loss of function, or (in some rare cases), even gain of function (summarised in (Courraud et al., 2021)). The effects of missense mutations depend on the protein domain of DYRK1A that is affected. For example, some mutations mainly affect the ability of DYRK1A to autophosphorylate itself at Tyr321 (Widowati et al., 2018).

3 Down syndrome

Down syndrome is the most common viable aneuploidy and is caused by full or partial trisomy of chromosome 21 (T21 or pT21) (Antonarakis, 1998; Papavassiliou et al., 2009; Papavassiliou et al.,2015; Antonarakis et al., 2020). DS is a multisystem disorder characterised by short stature, brachydactyly, hypotonia, a small mouth and ears, congenital heart defects, hypothyroidism, obstructive sleep apnoea, epilepsy, hearing and vision problems, haematological disorders, anxiety disorders, early-onset Alzheimer disease, and autism spectrum disorder (Antonarakis et al., 2020). Interestingly, the majority of these features of DS were also observed in individuals with pT21 (Lyle et al., 2009; Pelleri et al., 2019; Pelleri et al.,2022; Murray et al., 2023), particularly in cases involving duplication of the Down syndrome critical region (DSCR) located on chromosome 21q22.13 (Antonaros et al., 2021) including DYRK1A which is one of the most important genes responsible for the neurodevelopmental and cognitive features associated with DS (Ronan et al., 2009; Schnabel et al., 2018; Murray et al., 2023).

4 In vitro modelling

In vitro models have been one of key tools in understanding how altered DYRK1A dosage contributes to DS and DYRK1A syndrome phenotypes. Previously, transchromosomic mouse (Canzonetta et al., 2008) as well as mouse and human embryonic stem cells (mESCs and hESCs) were commonly used to study DS-specific phenotypes in vitro (Canzonetta et al., 2008; Halevy et al., 2016; Smith et al., 2025). However, the use of hESCs has become more limited due to ethical concerns. An early study using three cell lines (HeLa, U2OS, and HEK-293T) contributed to the identification of molecular targets of DYRK1A . For example, RNF169 was identified as a DYRK1A substrate, revealing an important role of DYRK1A in regulation of the cellular DNA damage response (Menon et al., 2019; Roewenstrunk et al., 2019). Moreover, several studies conducted in different cell lines, including both mouse and human cells, have identified DYRK1A as a negative regulator of the G1/S transition of the cell cycle. DYRK1A induces G1-phase cell cycle arrest by directly phosphorylating Cyclin D1, thereby promoting its degradation and inhibiting cell cycle progression (Park et al., 2010; Chen et al., 2013; Fernández-Martínez et al., 2015; Vorwerk et al., 2024; Hammond et al., 2026).

The discovery of both mouse (Takahashi and Yamanaka, 2006) and human (Takahashi et al., 2007; Yu et al., 2007) induced pluripotent stem cells (iPSCs) represents one of the most significant breakthroughs in modern science. Over the last two decades several DS hiPSCs have been generated and published (Park et al., 2008; Li et al., 2012; Briggs et al., 2013; Kogut et al., 2018; Ovchinnikov et al., 2018; Yu et al., 2023). Importantly, rare DS isogenic hiPSC lines (Weick et al., 2013; Murray et al., 2015; 2023; Huo et al., 2018; Giffin-Rao et al., 2022) were also generated, providing a valuable biological platform for investigating the role of T21 and/or specific genetic variants in the development of particular phenotypes. Additionally to DS iPSCs, new iPSCs from individuals with DYRK1A syndrome (Ge et al., 2024; Peng et al., 2026) were published.

Recently, significantly increased DNA damage, together with abnormalities of the nuclear envelope labelled with Lamin B1, was demonstrated using two isogenic DS hiPSC models (Murray et al., 2023). Remarkably, this cellular phenotype was rescued by treating with DYRK1A inhibitors in hiPSCs and cerebral organoids (Harmine and ID-8), or by CRISPR/Cas9-mediated gene-editing of DYRK1A in the hiPSCs (Murray et al., 2023). Interestingly, reintroduction of DYRK1A by plasmid transfection (Rozen et al., 2018) into DYRK1A knockout (KO) hiPSCs increased DNA damage (Murray et al., 2023). Importantly, the in vitro findings were validated in primary blood cells obtained from an individual with pT21, as well as in human brain and liver tissues collected from individuals with DS and age/sex-matched euploid controls. Finally, reduced DYRK1A dosage in pT21 cerebral organoids resulted in a microcephaly-like phenotype and increased cortical gyrification (Murray et al., 2023).

Moreover, it was shown that Leucettinib-21 reduces the activity of DYRK1A as well as phosphorylation of the Cyclin D1 in human isogenic iPSCs derived neural progenitor cells (Giffin-Rao et al., 2022; West et al., 2026), while in the cortical neurons along with reduced activity it decreases Tau phosphorylation.

5 Animal modelling

HSA21 is the smallest human autosome, containing 235 protein-coding genes, 441 non-coding RNA genes and 188 pseudogenes (Hattori et al., 2000; Howe et al., 2021). The syntenic regions of HSA21 are distributed across three mouse chromosomes: mouse chromosome 16 (Mmu16), mouse chromosome 17 (Mmu17) and mouse chromosome 10 (Mmu10) (Canonica et al., 2024). Mouse Dyrk1a is located on Mmu16 (Reeves et al., 1995). Over the past three decades, numerous animal models have been developed and extensively used in research. The pioneering study using Drosophila mini brain (mnb) demonstrated altered neural proliferation and reduced brain size (Tejedor et al., 1995) which is the Drosophila orthologue of mammalian DYRK1A (Tejedor and Hämmerle, 2011).

The Ts65Dn (B6EiC3Sn a/A-Ts (1716) 65Dn/J) mouse has widely used as an animal model of DS (Reeves et al., 1995; Duchon et al., 2011). Due to the overexpression of Dyrk1a in Ts65Dn mice, several studies reported increased Tau expression, increased Tau phosphorylation and an altered ratio of 3R-Tau to 4R-Tau, which was deemed to contribute to neurodegenerative changes in the DS nervous system (Liu et al., 2008; Qian et al., 2013; Yin et al., 2017). In addition to Tau pathology, Ts65Dn mice exhibited morphological and functional retinal alterations similar to those observed in individuals with DS, including increased retinal size and cellularity, together with impaired Caspase-9-mediated apoptosis (Laguna et al., 2013). Moreover, the same study showed that another mouse model, transgenic Dyrk1a (i.e., transgenic mice carrying one additional copy of the Dyrk1a gene), exhibited a similar phenotype (Laguna et al., 2013). Dyrk1a dosage normalisation in Ts65Dn mice rescued both the morphological and functional phenotypes. In contrast, Dyrk1a +/− (haploinsufficiency) mice exhibited significantly thinner inner nuclear and inner plexiform layers, together with an increased number of Caspase-9-positive cells. These findings emphasise the role of Dyrk1a during retinal development (Laguna et al., 2008; Laguna et al.,2013). The same two mouse strains, Ts65Dn and transgenic Dyrk1a, were used in a study that analysed the role of Dyrk1a in the cell cycle and differentiation of cortical neurons. Interestingly, the study showed that neocortical radial glial progenitors in transgenic Dyrk1a embryos had lower nuclear Cyclin D1 levels than those in the control embryos, along with a longer cell cycle duration. Moreover, the transgenic animals exhibited altered neurogenesis, characterised by a significantly higher number of Tbr2 positive cells and a significantly lower number of Tbr1 positive cells. These changes contribute to a shift towards gliogenesis and an altered proportion of neuronal projections. Furthermore, normalisation of Dyrk1a gene dosage restored Cyclin D1 levels and neuronal differentiation in Ts65Dn embryos. Overall, these findings emphasise the role of Dyrk1a in the proliferation and differentiation of cortical neurons (Najas et al., 2015). Additional to a gliogenic shift, Dyrk1a +/− mice showed neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviours and epileptic activity (Pijuan et al., 2022). Dyrk1a overexpression in transgenic Dyrk1a mice contributes in DS motor phenotypes, especially in motor cholinergic neurons (Arque et al., 2013).

Recently, seven new mouse strains carrying different HSA21-syntenic regions were generated (Lana-Elola et al., 2016). One of these, the Dp1Tyb strain, showed reduced expression of genes involved in mitochondrial respiration and cell proliferation. The same study demonstrated that an increased dosage of Dyrk1a was one of the contributing factors to congenital heart defects in Dp1Tyb mice comparable to those observed in individuals with DS (Lana-Elola et al., 2024). In addition to the heart defects, Dp1Tyb mice have wide range of DS specific features, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep (Lana-Elola et al., 2021). The same mouse strain, Dp1Tyb, exhibited DS-specific craniofacial morphology similar to that observed in individuals with DS, associated with increased Dyrk1a dosage. In addition to these morphological abnormalities, the authors demonstrated impaired neural crest cell proliferation, which is particularly important because many craniofacial structures are derived from the neural crest (Redhead et al., 2023). Enlarged early endosomes and elevated levels of active Rab5 in Dp1Tyb basal forebrain neurons were associated with impaired transport of internalised TrkB from axons to the soma (Blackburn et al., 2026). Finally, the increased GABA inhibition in Dp1Tyb dentate gyrus is caused by overexpression of Olig1, Olig2 and Dyrk1a (Hannan et al., 2025).

The most recent Down syndrome-Alzheimer’s disease (DSAD) mouse models with humanized amyloid precursor protein (APP)/amyloid-β (Aβ) have been generated. Those two models exhibit early AD features and show an overexpression of Dyrk1a (Baniowska et al., 2026).

Although different mouse models of DS have been widely used in many studies, several rat models of DS have recently been developed. Compared with mice, rats are larger animals while recapitulating the DS phenotype, making them advantageous for studies that require more complex behavioural, physiological or surgical procedures (Birling et al., 2017; Kazuki et al., 2022; Raza et al., 2026).

6 Comparison of model accuracy

Over the last 160 years, since DS was first described by John Langdon Down, and its genetic cause by Jérôme Lejeune, a wide range of animal and human models have been developed to investigate the underlying mechanisms of the disorder. Some of these models are summarised in Table 1. Other animal models also used in DS research are also explained in (Raza et al., 2026). Initially, animal models, particularly mice, were more prevalent in the scientific literature. One of the most widely used models is the Ts65Dn mouse (Reeves et al., 1995), which carries an additional chromosome segment and is trisomic for a region of mouse chromosome Mmu16 that is orthologous to Hsa21. Though very useful for understanding of many DS phenotypes, this model contains an additional set of overdosed genes not from human chromosome 21, making it not entirely specific to the effects of human chromosome 21 triplication. This limitation was not initially recognised. Several other, above mentioned, models have also been used to investigate the role of DYRK1A in DS. Interestingly, the Dp1Tyb strain carries an extra copy of approximately 63% of Hsa21-orthologous mouse genes and significantly recapitulates several DS-related phenotypes, including congenital heart defects and altered head morphology (Lana-Elola et al., 2016; Lana-Elola et al.,2024). This makes Dp1Tyb one of the most promising mouse models for studying DS, particularly in the context of DYRK1A. Although animal models are indispensable because they enable the investigation of DYRK1A in a living organism and therefore allow a more comprehensive understanding of its molecular and pathophysiological mechanisms, one of their major limitations is the lack of complete synteny between Hsa21 and the corresponding rodent chromosomes. In addition, complete knockout of Dyrk1a in mice is lethal, which limits the feasibility of studies investigating the consequences of complete DYRK1A loss in vivo.

TABLE 1. Summary of experimental models of both syndromes shown in this manuscript.

Experimental modelSyndromeDYRK1A copy numberFeaturesReferences
HumanDST21-3xDYRK1ASeveral DS models showed altered expression and downstream signaling of NRSF/REST an alteration in T21 cells throughout differentiation, as a function of DYRK1A overdoseCanzonetta et al. (2008); Lepagnol-Bestel et al. (2009); Lu et al. (2011)
DSD21-2xDYRK1AT21-3xDYRK1AHuman isogenic T21 iPSCs-derived neurons showed significantly higher amyloid beta expression and DNA damageMurray et al. (2015)
DSD21-2xDYRK1AT21-3xDYRK1AT21-1xDYRK1AT21-0xDYRK1A pT21-3xDYRK1ApT21-1xDYRK1AHuman isogenic T21 iPSCs showed significant changes in DNA damage, shape of nuclear envelope and cerebral organoid size and gyrification under the influence of DYRK1AMurray et al. (2023)
DYRK1A syndromeD21-1xDYRK1ARecently generated iPSCs from a patient with DYRK1A syndrome carrying a heterozygous DYRK1A mutation (c.1024G > T)Ge et al. (2024)
DYRK1A syndromeD21-1xDYRK1ARecently generated iPSCs from a patient with DYRK1A syndrome carrying a heterozygous DYRK1A mutation (c.1042G>A)Peng et al. (2026)
AnimalDS -Ts65DnT21-3xDyrk1aOne of the most widely used mouse DS models in biomedical researchReeves et al. (1995)
DS -Ts65Dn and transgenic model mBACtgDyrk1aT21-3xDyrk1aT21-2xDyrk1aT21-1xDyrk1aTrisomy of Dyrk1a is necessary and sufficient for abnormal retinal phenotype which were corrected by Dyrk1a gene editingLaguna et al. (2008) ; Laguna et al. (2013)
DS -Ts65Dn and transgenic model mBACtgDyrk1aT21-3xDyrk1aT21-2xDyrk1aT21-1xDyrk1aNormalisation of Dyrk1a gene dosage restored Cyclin D1 levels and neuronal differentiation in these animal modelsNajas et al. (2015)
DS -Dp1TybT21-3xDyrk1aOne of the most recent mouse models which showed congenital heart defects caused by increased dose of DYRK1ALana-Elola et al. (2016) ; Lana-Elola et al. (2024)
DS -Dp1TybT21-3xDyrk1aOne of the most recent mouse models which showed specific cranio-facial morphologyRedhead et al. (2023); Otte and Roper, (2024)

In contrast, human models, particularly induced iPSC-derived models, have only been widely used for approximately the last decade. These models enable the investigation of DYRK1A in human cells, and advances in CRISPR/Cas9 gene editing, together with the development of DYRK1A inhibitors, have facilitated studies in a variety of iPSC-derived cell types (Murray et al., 2023). Particularly promising are recently published iPSC lines derived from individuals with DYRK1A syndrome (Ge et al., 2024; Peng et al., 2026), which provide an opportunity to investigate the effects of DYRK1A dysfunction in a human genetic context. However, the major limitation of human iPSC-based models is the lack of complex tissue organisation, regardless of the tissue or cell type being studied. Based on the available evidence, both animal and human models have distinct advantages and limitations and should not be considered mutually exclusive. Rather, an integrated approach combining different model systems is likely to be necessary to obtain a comprehensive understanding of DS and the role of DYRK1A in its pathophysiology.

7 Discussion

Dysregulation of DYRK1A has been linked to numerous human disorders. Intriguingly, increased DYRK1A dosage resulting from trisomy 21, contributes to Down syndrome-associated phenotypes, whereas DYRK1A haploinsufficiency, causes DYRK1A syndrome. DYRK1A is highly expressed during embryonic development and continues to be expressed throughout adulthood, reflecting its involvement in numerous essential biological processes. Because proper physiological function requires a tightly regulated DYRK1A dosage, this gene has been described as a “Goldilocks gene” (Johnson et al., 2025), as both increased and decreased expression levels can result in pathological consequences. A comprehensive review of the literature, together with our own findings, indicates that despite representing opposite alterations in gene dosage, DYRK1A haploinsufficiency and T21 share several overlapping clinical features. Notably, intellectual disability and autism spectrum disorder are among the most prominent shared phenotypes. Microcephaly represents one of the cardinal features of DYRK1A syndrome; although it is not considered a typical feature of DS, individuals with DS frequently exhibit reduced brain volume with diminished gyrification compared with euploid controls (Pinter et al., 2001; Hamner et al., 2018; Rodrigues et al., 2019; Levman et al., 2024). A similar pattern has also been observed throughout in vitro differentiation of human isogenic cortico-striatal spheroids and assembloids (Plećaš et al., 2026). Additional partially overlapping phenotypes include congenital septal heart defects, urogenital abnormalities, short stature, and several other developmental abnormalities. Taken together, these observations emphasize that DYRK1A is an exceptionally dosage-sensitive gene that plays essential roles from embryonic development through adulthood. Perhaps the most intriguing aspect is that both reduced and increased DYRK1A dosage, haploinsufficiency and T21 respectively, can lead to remarkably similar clinical features. This paradox represents a major gap in our current understanding and raises important biological questions regarding the molecular mechanisms underlying these shared phenotypes. The development of advanced in vitro disease models, particularly patient-derived hiPSCs combined with CRISPR/Cas9 genome-editing technology (Murray et al., 2023), now provides an unprecedented opportunity to model these syndromes in vitro. The main limitation of in vitro models is that they cannot fully reproduce the complexity of whole-organism development due to absence of blood vessels, the heart, and connective tissue; therefore, animal models are necessary for in vivo studies. Together, these complementary platforms enable detailed investigation of cellular proliferation, differentiation, neurodevelopmental and neurodegenerative processes, ultimately facilitating the identification of novel therapeutic targets and supporting the development of treatments that may progress to future clinical trials.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Anton Tonchev, Medical University of Varna, Bulgaria

Reviewed by: Jérémie Courraud, University of Calgary, Canada

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. AP’s and IA’s work was funded by Adris foundation, NPOO-NextGeneration (NPOO – 12, NEURO-MORF), Croatian Science Foundation (HRZZ-UIP-2025-02-5828) and CRP-ICGEB (CRP/HRV25-03); DN’s work was funded by a Wellcome Trust Collaborative Award in Science 217199/Z/19/Z.

Author contributions

AP: Writing – review and editing, Writing – original draft, Conceptualization, Funding acquisition. GG: Visualization, Software, Writing – review and editing. SK: Writing – review and editing. MB: Writing – review and editing. AM: Writing – review and editing. DN: Writing – review and editing. IA: Resources, Writing – original draft, Funding acquisition, Conceptualization, Project administration, Writing – review and editing, Supervision, Investigation.

References

  1. Antonarakis S. E. (1998). 10 years of genomics, chromosome 21, and Down syndrome. Genomics 51 (1), 1 – 16. doi:10.1006/GENO.1998.5335
  2. Antonarakis S. E., Skotko B. G., Rafii M. S., Strydom A., Pape S. E., Bianchi D. W. (2020). Down syndrome. Nat. Rev. Dis. Prim. 6 (1), 1 – 20. doi:10.1038/s41572-019-0143-7
  3. Antonaros F., Pitocco M., Abete D., Vione B., Piovesan A., Vitale L. (2021). Structural characterization of the highly restricted Down syndrome critical region on 21q22.13: New KCNJ6 and DSCR4 transcript isoforms. Front. Genet. 12, 770359. doi:10.3389/FGENE.2021.770359
  4. Arque G., Casanovas A., Dierssen M. (2013). Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome. PLoS ONE 8 (1), 54285. doi:10.1371/journal.pone.0054285
  5. Atas-Ozcan H., Brault V., Duchon A., Herault Y. (2021). Dyrk1a from gene function in development and physiology to dosage correction across life span in Down syndrome. Genes 12, 1833. doi:10.3390/genes12111833
  6. Baniowska M. R., Mumford P., Prestia F., Stephan P., Beament M., Birling M. (2026). Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer’s disease in Down syndrome. Alzheimer’s and Dementia The Journal Alzheimer’s Assoc. 22 (5), e71498. doi:10.1002/ALZ.71498
  7. Bellmaine S. F., Ovchinnikov D. A., Manallack D. T., Cuddy C. E., Elefanty A. G., Stanley E. G. (2017). Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells. eLife 6, e24502. doi:10.7554/ELIFE.24502
  8. Birling M. C., Schaeffer L., André P., Lindner L., Maréchal D., Ayadi A. (2017). Efficient and rapid generation of large genomic variants in rats and mice using CRISMERE. Sci. Rep. 7 (1), 43331. doi:10.1038/srep43331
  9. Blackburn E., Birsa N., Lopes A. T., Fisher E. M. C., Lazo O. M., Schiavo G. (2026). Impaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons. Cell Death and Disease 17 (1), 214. doi:10.1038/S41419-026-08464-Z
  10. Briggs J. A., Mason E. A., Ovchinnikov D. A., Wells C. A., Wolvetang E. J. (2013). Concise review: new paradigms for Down syndrome research using induced pluripotent stem cells: tackling complex human genetic disease. Stem Cells Transl. Med. 2 (3), 175 – 184. doi:10.5966/SCTM.2012-0117
  11. Canonica T., Kidd E. J., Gibbins D., Lana-Elola E., Fisher E. M. C., Tybulewicz V. L. J. (2024). Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome. Front. Behavioral Neuroscience 18, 1428146. doi:10.3389/FNBEH.2024.1428146
  12. Canzonetta C., Mulligan C., Deutsch S., Ruf S., O'Doherty A., Lyle R. (2008). DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am. Journal Human Genetics 83 (3), 388 – 400. doi:10.1016/J.AJHG.2008.08.012
  13. Chen J. Y., Lin J. R., Tsai F. C., Meyer T. (2013). Dosage of Dyrk1a shifts cells within a p21-Cyclin D1 signaling map to control the decision to enter the cell cycle. Mol. Cell 52 (1), 87 – 100. doi:10.1016/J.MOLCEL.2013.09.009
  14. Cisternas P., Kim J., Ashfeld B., Zartman J. (2025). DYRK1A in the physiology and pathology of the neuron-astrocyte axis. Front. Neurosci. 19, 1626062. doi:10.3389/FNINS.2025.1626062
  15. Courraud J., Chater-Diehl E., Durand B., Vincent M., del Mar Muniz Moreno M., Boujelbene I. (2021). Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder. Genet. Med. 23 (11), 2150 – 2159. doi:10.1038/s41436-021-01263-1
  16. Courraud J., Quartier A., Drouot N., Zapata-Bodalo I., Gilet J., Benchoua A. (2025). DYRK1A roles in human neural progenitors. Front. Neurosci. 19, 1533253. doi:10.3389/FNINS.2025.1533253
  17. Duchon A., Raveau M., Chevalier C., Nalesso V., Sharp A. J., Herault Y. (2011). Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mammalian Genome Official J. Int. Mammalian Genome Soc. 22 (11–12), 674 – 684. doi:10.1007/S00335-011-9356-0
  18. Fernández-Martínez P., Zahonero C., Sánchez-Gómez P. (2015). DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis. Mol. and Cell. Oncol. 2 (1), e970048. doi:10.4161/23723548.2014.970048
  19. Ge Y., Cheng Y., Yin T., Peng X., Xiong Z., Wu B. (2024). Generation of a human induced pluripotent stem cell line (FDCHi012-A) from a patient with DYRK1A-related intellectual disability syndrome carrying DYRK1A mutation (C.1024G > T). Stem Cell Res. 76, 103345. doi:10.1016/j.scr.2024.103345
  20. Giffin-Rao Y., Sheng J., Strand B., Xu K., Huang L., Medo M. (2022). Altered patterning of trisomy 21 interneuron progenitors. Stem Cell Reports 17 (6), 1366 – 1379. doi:10.1016/J.STEMCR.2022.05.001
  21. Glass O. K., Piton A., Pfalzer A. (2026). Editorial: advances in DYRK1A syndrome: underlying mechanisms, disease models, and novel therapeutic approaches. Front. Neurosci. 20, 1803346. doi:10.3389/FNINS.2026.1803346/TEXT
  22. Guedj F., Pereira P. L., Najas S., Barallobre M. J., Chabert C., Souchet B. (2012). DYRK1A: a master regulatory protein controlling brain growth. Neurobiol. Dis. 46 (1), 190 – 203. doi:10.1016/J.NBD.2012.01.007
  23. Halevy T., Biancotti J. C., Yanuka O., Golan-Lev T., Benvenisty N. (2016). Molecular characterization of Down syndrome embryonic stem cells reveals a role for RUNX1 in neural differentiation. Stem Cell Rep. 7 (4), 777 – 786. doi:10.1016/J.STEMCR.2016.08.003
  24. Hammond T., Choi J. B., Membreño M. W., Demeter J., Ng R., Bhattacharya D. (2026). The FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle. eLife 14, RP109708. doi:10.7554/ELIFE.109708
  25. Hamner T., Udhnani M. D., Osipowicz K. Z., Lee N. R. (2018). Pediatric brain development in Down syndrome: a field in its infancy. J. Int. Neuropsychological Soc. JINS 24 (9), 966 – 976. doi:10.1017/S1355617718000206
  26. Hannan S. B., Lana-Elola E., Watson-Scales S., Fisher E. M., Tybulewicz V. L., Smart T. G. (2025). Hippocampal circuit-specific enhancement of GABA-Inhibition caused by discrete gene regions in a Down syndrome model. bioRxiv, 2025. doi:10.1101/2025.07.21.665861
  27. Hattori M., Fujiyama A., Taylor T. D., Watanabe H., Yada T., Park H. S. (2000). The DNA sequence of human chromosome 21. Nature 405 (6784), 311 – 319. doi:10.1038/35012518
  28. Howe K. L., Achuthan P., Allen J., Allen J., Alvarez-Jarreta J., Amode M. R. (2021). Ensembl 2021. Nucleic Acids Research 49 (D1), D884 – D891. doi:10.1093/NAR/GKAA942
  29. Huo H. Q., Qu Z. Y., Yuan F., Ma L., Yao L., Xu M. (2018). Modeling Down syndrome with patient iPSCs reveals cellular and migration deficits of GABAergic neurons. Stem Cell Reports 10 (4), 1251 – 1266. doi:10.1016/J.STEMCR.2018.02.001
  30. Ji J., Lee H., Argiropoulos B., Dorrani N., Mann J., Martinez-Agosto J. A. (2015). DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur. J. Hum. Genet. 23 (11), 1473 – 1481. doi:10.1038/ejhg.2015.71
  31. Johnson H. K., Litovchick L. L., Dickinson A. J. G. (2025). The role of goldilocks protein kinase DYRK1A in embryonic development. Dev. Biol. 525, 216 – 228. doi:10.1016/J.YDBIO.2025.06.009
  32. Kazuki Y., Gao F. J., Yamakawa M., Hirabayashi M., Kazuki K., Kajitani N. (2022). A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features. Am. J. Hum. Genet. 109 (2), 328 – 344. doi:10.1016/j.ajhg.2021.12.015
  33. Kogut I., McCarthy S. M., Pavlova M., Astling D. P., Chen X., Jakimenko A. (2018). High-efficiency RNA-Based reprogramming of human primary fibroblasts. Nat. Commun. 9 (1), 745. doi:10.1038/S41467-018-03190-3
  34. Kurtz-Nelson E. C., Rea H. M., Petriceks A. C., Hudac C. M., Wang T., Earl R. K. (2023). Characterizing the autism spectrum phenotype in DYRK1A-related syndrome. Autism Res. 16 (8), 1488 – 1500. doi:10.1002/AUR.2995
  35. Laguna A., Aranda S., Barallobre M. J., Barhoum R., Fernández E., Fotaki V. (2008). The protein kinase DYRK1A regulates Caspase-9-Mediated apoptosis during retina development. Dev. Cell 15 (6), 841 – 853. doi:10.1016/j.devcel.2008.10.014
  36. Laguna A., Barallobre M. J., Marchena M. Á., Mateus C., Ramírez E., Martínez-Cue C. (2013). Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome. Hum. Mol. Genet. 22 (14), 2775 – 2784. doi:10.1093/HMG/DDT125
  37. Lana-Elola E., Watson-Scales S., Slender A., Gibbins D., Martineau A., Douglas C. (2016). Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel. eLife 5, e11614. doi:10.7554/ELIFE.11614
  38. Lana-Elola E., Cater H., Watson-Scales S., Greenaway S., Müller-Winkler J., Gibbins D. (2021). Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes. Dis. Models and Mechanisms 14 (10), dmm049157. doi:10.1242/DMM.049157
  39. Lana-Elola E., Aoidi R., Llorian M., Gibbins D., Buechsenschuetz C., Bussi C. (2024). Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Sci. Transl. Med. 16 (731), 6883. doi:10.1126/SCITRANSLMED.ADD6883
  40. Le May N., Courraud J., Boujelbène I., Obringer C., Ogi T., Lehmann A. R. (2025). Clinical and molecular overlap between nucleotide excision repair (NER) disorders and DYRK1A haploinsufficiency syndrome. Front. Neuroscience 19, 1554093. doi:10.3389/FNINS.2025.1554093
  41. Lepagnol-Bestel A. M., Zvara A., Maussion G., Quignon F., Ngimbous B., Ramoz N. (2009). DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Hum. Molecular Genetics 18 (8), 1405 – 1414. doi:10.1093/HMG/DDP047
  42. Levman J., McCann B., Baumer N., Lam Y. M., Shiohama T., Cogger L. (2024). Structural magnetic resonance imaging-based surface morphometry analysis of pediatric Down syndrome. Biology 13 (8), 575. doi:10.3390/BIOLOGY13080575
  43. Li L. B., Chang K. H., Wang P. R., Hirata R. K., Papayannopoulou T., Russell D. W. (2012). Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell 11 (5), 615 – 619. doi:10.1016/J.STEM.2012.08.004
  44. Liu F., Liang Z., Wegiel J., Hwang Y. W., Iqbal K., Grundke-Iqbal I. (2008). Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB Journal Official Publication Fed. Am. Soc. Exp. Biol. 22 (9), 3224 – 3233. doi:10.1096/FJ.07-104539
  45. Lu M., Zheng L., Han B., Wang L., Wang P., Liu H. (2011). REST regulates DYRK1A transcription in a negative feedback loop. J. Biol. Chem. 286 (12), 10755 – 10763. doi:10.1074/jbc.M110.174540
  46. Luco S. M., Pohl D., Sell E., Wagner J. D., Dyment D. A., Daoud H. (2016). Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature. BMC Med. Genet. 17 (1), 15. doi:10.1186/S12881-016-0276-4
  47. Lyle R., Béna F., Gagos S., Gehrig C., Lopez G., Schinzel A. (2009). Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur. Journal Human Genetics EJHG 17 (4), 454 – 466. doi:10.1038/EJHG.2008.214
  48. Meissner L. E., Macnamara E. F., D'Souza P., Yang J., Vezina G., Ferreira C. R. (2020). DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature. Mol. Genetics and Genomic Medicine 8 (12), e1544. doi:10.1002/MGG3.1544
  49. Menon R., Ananthapadmanabhan V., Swanson S., Saini S., Sesay F., Yakovlev V. (2019). DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169. Cell Cycle, 18 (5), 531 – 551. doi:10.1080/15384101.2019.1577525
  50. Møller R. S., Kübart S., Hoeltzenbein M., Heye B., Vogel I., Hansen C. P. (2008). Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am. J. Hum. Genet. 82 (5), 1165 – 1170. doi:10.1016/j.ajhg.2008.03.001
  51. Murray A., Letourneau A., Canzonetta C., Stathaki E., Gimelli S., Sloan-Bena F. (2015). Brief report: Isogenic induced pluripotent stem cell lines from an adult with mosaic Down syndrome model accelerated neuronal ageing and neurodegeneration. STEM CELLS 33, 2077 – 2084. doi:10.1002/stem.1968
  52. Murray A., Gough G., Cindrić A., Vučković F., Koschut D., Borelli V. (2023). Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels. eBioMedicine 94, 104692. doi:10.1016/j.ebiom.2023.104692
  53. Najas S., Arranz J., Lochhead P. A., Ashford A. L., Oxley D., Delabar J. M. (2015). DYRK1A-mediated cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in Down syndrome. EBioMedicine 2 (2), 120 – 134. doi:10.1016/J.EBIOM.2015.01.010
  54. Otte E. D., Roper R. J. (2024). Skeletal health in DYRK1A syndrome. Front. Neuroscience 18, 1462893. doi:10.3389/FNINS.2024.1462893
  55. Ovchinnikov D. A., Korn O., Virshup I., Wells C. A., Wolvetang E. J. (2018). The impact of APP on alzheimer-like pathogenesis and gene expression in Down syndrome iPSC-Derived neurons. Stem Cell Rep. 11 (1), 32 – 42. doi:10.1016/j.stemcr.2018.05.004
  56. Papavassiliou P., York T. P., Gursoy N., Hill G., Nicely L. V., Sundaram U. (2009). The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Am. J. Med. Genet. Part 149A (4), 573 – 583. doi:10.1002/AJMG.A.32729
  57. Papavassiliou P., Charalsawadi C., Rafferty K., Jackson-Cook C. (2015). Mosaicism for trisomy 21: a review. Am. J. Med. Genet. Part A 167 (1), 26 – 39. doi:10.1002/AJMG.A.36861
  58. Park I. H., Arora N., Huo H., Maherali N., Ahfeldt T., Shimamura A. (2008). Disease-specific induced pluripotent stem cells. Cell 134 (5), 877 – 886. doi:10.1016/J.CELL.2008.07.041
  59. Park J., Oh Y., Yoo L., Jung M. S., Song W. J., Lee S. H. (2010). Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. J. Biol. Chem. 285 (41), 31895 – 31906. doi:10.1074/JBC.M110.147520
  60. Pelleri M. C., Cicchini E., Petersen M. B., Tranebjaerg L., Mattina T., Magini P. (2019). Partial trisomy 21 map: ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21. Mol. Genet. and Genomic Med. 7 (8), e797. doi:10.1002/MGG3.797
  61. Pelleri M. C., Locatelli C., Mattina T., Bonaglia M. C., Piazza F., Magini P. (2022). Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype–phenotype association. BMC Med. Genomics 15 (1), 266. doi:10.1186/S12920-022-01422-6
  62. Peng X., Li Y., Zhang M., Wang H., Zhou W., Xiong M. (2026). Generation of a human induced pluripotent stem cell line (FDIBSi002-A) derived from a patient with DYRK1A carrying a heterozygous DYRK1A mutation (c.1042G>A). Stem Cell Res. 91, 103917. doi:10.1016/j.scr.2026.103917
  63. Pijuan I., Balducci E., Soto-Sánchez C., Fernández E., Barallobre M. J., Arbonés M. L. (2022). Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome. Sci. Rep. 12 (1), 19912. doi:10.1038/s41598-022-24284-5
  64. Pinter J. D., Eliez S., Schmitt J. E., Capone G. T., Reiss A. L. (2001). Neuroanatomy of down’s syndrome: a high-resolution MRI study. Am. J. Psychiatry 158 (10), 1659 – 1665. doi:10.1176/APPI.AJP.158.10.1659
  65. Plećaš A., Gough G., Grčević D., Jackowiak H., Skieresz-Szewczyk K., Horaček M. (2026). Abnormal neuronal and synaptic morphology in Down syndrome brains reproduces in human isogenic cellular models. Cell Death and Dis. 17 (1), 730. doi:10.1038/s41419-026-08956-y
  66. Qian W., Jin N., Shi J., Yin X., Jin X., Wang S. (2013). Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) enhances tau expression. J. Alzheimer’s Disease JAD 37 (3), 529 – 538. doi:10.3233/JAD-130824
  67. Raza M. A., Folz A., Victorino D. B., Xing Z., Chen X. Q., Zuo X. (2026). A Researcher’s guide to rodent models of Down syndrome: recent insights and translational perspectives. Star. Protoc. 7 (3), 104717. doi:10.1016/J.XPRO.2026.104717
  68. Redhead Y., Gibbins D., Lana-Elola E., Watson-Scales S., Dobson L., Krause M. (2023). Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes. Available A. T. 150, dev201077. doi:10.1242/dev.201077
  69. Reeves R. H., Irving N. G., Moran T. H., Wohn A., Kitt C., Sisodia S. S. (1995). A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat. Genetics 11 (2), 177 – 184. doi:10.1038/NG1095-177
  70. Rodrigues M., Nunes J., Figueiredo S., Martins de Campos A., Geraldo A. F. (2019). Neuroimaging assessment in Down syndrome: a pictorial review. Insights Into Imaging 10 (1), 1 – 13. doi:10.1186/S13244-019-0729-3
  71. Roewenstrunk J., Di Vona C., Chen J., Borras E., Dong C., Arató K. (2019). A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response. Sci. Rep. 9 (1), 6014. doi:10.1038/s41598-019-42445-x
  72. Ronan A., Fagan K., Christie L., Conroy J., Nowak N. J., Turner G. (2009). Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. BMJ Case Reports 2009. doi:10.1136/BCR.05.2009.1914
  73. Rozen E. J., Roewenstrunk J., Barallobre M. J., Di Vona C., Jung C., Figueiredo A. F. (2018). DYRK1A kinase positively regulates angiogenic responses in endothelial cells. Cell Rep. 23 (6), 1867 – 1878. doi:10.1016/J.CELREP.2018.04.008
  74. Schnabel F., Smogavec M., Funke R., Pauli S., Burfeind P., Bartels I. (2018). Down syndrome phenotype in a boy with a mosaic microduplication of chromosome 21q22. Mol. Cytogenetics 11 (1), 62. doi:10.1186/S13039-018-0410-4
  75. Smith G. D., Keller L., Hergenreder T., Ye B. (2025). Down syndrome (trisomy 21) disease-specific human embryonic stem cell (hESC) lines, UMICHe003-A/UM152-1, UMICHe004-A/UM202-1, and UMICHe005-A/UM229-1. Stem Cell Res. 88, 103831. doi:10.1016/J.SCR.2025.103831
  76. Takahashi K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (4), 663 – 676. doi:10.1016/J.CELL.2006.07.024
  77. Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131 (5), 861 – 872. doi:10.1016/J.CELL.2007.11.019
  78. Tejedor F. J., Hämmerle B. (2011). MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J. 278 (2), 223 – 235. doi:10.1111/J.1742-4658.2010.07954
  79. Tejedor F., Zhu X. R., Kaltenbach E., Ackermann A., Baumann A., Canal I. (1995). Minibrain: a new protein kinase family involved in postembryonic neurogenesis in drosophila. Neuron 14 (2), 287 – 301. doi:10.1016/0896-6273(95)90286-4
  80. Van Bon B. W. M., Hoischen A., Hehir-Kwa J., de Brouwer A. P. M., Ruivenkamp C., Gijsbers A. C. J. (2011). Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin. Genetics 79 (3), 296 – 299. doi:10.1111/J.1399-0004.2010.01544.X
  81. Varjosalo M., Keskitalo S., Van Drogen A., Nurkkala H., Vichalkovski A., Aebersold R. (2013). The protein interaction landscape of the human CMGC kinase group. Cell Rep. 3 (4), 1306 – 1320. doi:10.1016/j.celrep.2013.03.027
  82. Vorwerk V. A., Wilms G., Babendreyer A., Becker W. (2024). Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. Sci. Rep. 14 (1), 23926. doi:10.1038/s41598-024-74190-1
  83. Weick J. P., Held D. L., Bonadurer G. F., Doers M. E., Liu Y., Maguire C. (2013). Deficits in human trisomy 21 iPSCs and neurons. Proc. Natl. Acad. Sci. U. S. A. 110 (24), 9962 – 9967. doi:10.1073/PNAS.1216575110
  84. West N. R., Lindberg M. F., Dairou J., MacGregor S., Puthireddy S., Meijer L. (2026). Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 induced pluripotent stem cell-derived neural cells. Dis. Models and Mech. 19 (6), dmm052740. doi:10.1242/DMM.052740
  85. Widowati E. W., Ernst S., Hausmann R., Müller-Newen G., Becker W. (2018). Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. Biol. Open 7 (4). doi:10.1242/BIO.032862
  86. Yabut O., Domogauer J., D’Arcangelo G. (2010). Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J. Neurosci. 30 (11), 4004 – 4014. doi:10.1523/JNEUROSCI.4711-09.2010
  87. Yin X., Jin N., Shi J., Zhang Y., Wu Y., Gong C. X. (2017). Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice. Sci. Reports 7 (1), 619. doi:10.1038/S41598-017-00682-Y
  88. Yu J., Vodyanik M. A., Smuga-Otto K., Antosiewicz-Bourget J., Frane J. L., Tian S. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318 (5858), 1917 – 1920. doi:10.1126/SCIENCE.1151526
  89. Yu Y., Alonzo M., Ye S., Fang A., Manickam K., Garg V. (2023). Generation of an induced pluripotent stem cell line (NCHi010-A) from a 6-year-old female with Down syndrome and without congenital heart disease. Stem Cell Res. 71, 103155. doi:10.1016/J.SCR.2023.103155

Citation

Plećaš, A., et al. (2026). DYRK1A – a gene dose paradox. Frontiers in Cell and Developmental Biology, Volume 14. https://doi.org/
Received
Accepted
Published
Volume
14 - 2026

Copyright

Copyright © 2026 Plećaš, Gough, Kunštek, Babić, Murray, Nižetić and Alić.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Ante Plećaš; Dean Nižetić; Ivan Alić

Article metrics

Views
0
Downloads
0
Citations
0
Shares
0

Related articles

Original ResearchConserved phosphorylation events in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cellsHaojie Duan, Qian Wang, Yuping Suo, Jin-An Zhou, Xiaojuan Liu, Yin FangReviewLysine lactylation in glioma: from metabolic stress to epigenetic remodeling and therapeutic resistanceXiaosong Hu, Li Yang, Yanghao Hu, Hongjuan CuiReviewExtracellular vesicles in colorectal cancer: M2 polarization, bidirectional regulation of CAFs, metastasis, and treatmentXiaoling Wang, Zhaohua Lai, Hanlu Chen, Mei Yang, Huapei Kang, Fangsheng Wang, Junyun Huang, Yuxin Deng