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Background:
Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial featur...
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Citations
... Loss of function mutations in DYRK1A that lead to decreased DYRK1A protein levels result in primary microcephaly and developmental delays, reminiscent of mnb mutant phenotypes (8,12,14). Given its disease phenotypes, it is clear that DYRK1A plays a critical role in neuronal development and physiology. ...
The human dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in the pathology of Down syndrome, microcephaly, and cancer, however the exact mechanism through which it functions is unknown. Here, we have studied the role of the Drosophila ortholog of DYRK1A, Minibrain (Mnb), in brain development. The neuroblasts (neural stem cells) that eventually give rise to differentiated neurons in the adult brain are formed from a specialized tissue in the larval optic lobe called the neuroepithelium, in a tightly regulated process. Molecular marker analysis of mnb mutants revealed alterations in the neuroepithelium and neuroblast regions of developing larval brains. Using affinity purification-mass spectrometry (AP-MS), we identified the novel Mnb binding partners Ral interacting protein (Rlip) and RALBP1 associated Eps domain containing (Reps). Rlip and Reps physically and genetically interact with Mnb, and the three proteins may form a ternary complex. Mnb phosphorylates Reps, and human DYRK1A binds to the Reps orthologs REPS1 and REPS2. Furthermore, Mnb engages the small GTPase Ras-like protein A (Rala) to regulate brain and wing development. This work uncovers a previously unrecognized early role of Mnb in the neuroepithelium and defines the functions of the Mnb/Reps/Rlip/Rala signaling network in brain development.
Significance statement
The kinase Minibrain(Mnb)/DYRK1A regulates the development of the brain and other tissues across many organisms. Here we show the critical importance of Mnb within the developing neuroepithelium. Advancing our understanding of Mnb function, we identified novel protein interactors of Mnb, Reps and Rlip, which function together with Mnb to regulate growth in Drosophila melanogaster . We also identify and characterize a role for the small GTPase Rala in Mnb-regulated growth and nervous system development. This work reveals an early role of Mnb in brain development and identifies a new Mnb/Reps/Rlip/Rala signaling axis.
... Moreover, patients harboring DYRK1A mutations consistently exhibit developmental delays, speech impairments, and refractory epilepsy, as observed in our case. These manifestations highlight the neurological impact of DYRK1A on cognitive and motor functions, posing diagnostic and therapeutic challenges [4]. ...
Autosomal Dominant Mental Retardation Type 7 is a disorder caused by pathogenic variants in the DYRK1A gene. Clinical features associated with this gene mutation include focal dysmorphism, developmental delay, and epilepsy. In this report, we present a case of an 8-year-old boy with a DYRK1A gene mutation, whose clinical manifestations underscore the rarity and clinical challenges of this genetic condition. The patient is a known case of global developmental delay with intractable epilepsy on multiple anti-epileptic medications. Upon examination, the patient showed delayed developmental milestones, hypotonia with brisk deep tendon reflexes, as well as dysmorphic features in the form of microcephaly, deep-set eyes, prominent ears, and a short nose. MRI was done, and findings were suggestive of a DYRK1A gene mutation. The diagnosis was later confirmed by Whole Exome Sequencing (WES). Our report aims to contribute to the growing knowledge about DYRK1A mutations, facilitating a better understanding of the associated clinical features and implications for patient care.
... Several publications refer to a typical gestalt or common dysmorphisms 1,3,13,15,18,20 . All patients in this report had a thin upper lip, and deep-set eyes were described in all but one (Fig. 1). ...
... In the present paper, we aim to highlight unusual anomalies associated with a DYRK1A mutation: a 17-year-old female patient with language and cognitive delay, microcephaly, and an autistic disorder, who was operated upon for spleen torsion with anomalous gut fixation. KEYWORDS spleen abnormalities, gut abnormalities, DYRK1A, intestinal obstruction, splenectomy Background DYRK1A is a gene located on the critical region of chromosome 21q22 (1). It codifies for a dual-specificity tyrosine kinase, enrolled in the phosphorylation of serine and threonine residues (2,3) and tyrosine residues in their own loop (3). ...
DYRK1A syndrome has been extensively studied primarily with regard to neurologic and other phenotypic features such as skeleton and craniofacial alterations. In the present paper, we aim to highlight unusual anomalies associated with a DYRK1A mutation: a 17-year-old female patient with language and cognitive delay, microcephaly, and an autistic disorder, who was operated upon for spleen torsion with anomalous gut fixation.
... These highly debilitating conditions affect 1-3% of the world's population and have no cure or treatment (Ropers & Hamel, 2005;Picker & Walsh, 2013). A significant proportion of these disorders have an underlying genetic origin (Delaunoy et al, 2001;Hackett et al, 2010;Ellison et al, 2013;Gonçalves et al, 2014;Luco et al, 2016) with frequent disruption to genes encoding ubiquitylation components, underscoring its importance in this disease setting (Froyen et al, 2008;Geetha et al, 2014;Bramswig et al, 2017;Santiago-Sim et al, 2017;Tsurusaki et al, 2017;Zhang et al, 2017;Fountain et al, 2019;Geerts-Haages et al, 2020;Johnson et al, 2020;Suzuki et al, 2020;Beck et al, 2021;Li et al, 2021). ...
Ubiquitylation enzymes are involved in all aspects of eukaryotic biology and are frequently disrupted in disease. One example is the E3 ubiquitin ligase RNF12/RLIM, which is mutated in the developmental disorder Tønne-Kalscheuer syndrome (TOKAS). RNF12 TOKAS variants largely disrupt catalytic E3 ubiquitin ligase activity, which presents a pressing need to develop approaches to assess the impact of variants on RNF12 activity in patients. Here, we use photocrosslinking activity-based probes (photoABPs) to monitor RNF12 RING E3 ubiquitin ligase activity in normal and pathogenic contexts. We demonstrate that photoABPs undergo UV-induced labelling of RNF12 that is consistent with its RING E3 ligase activity. Furthermore, photoABPs robustly report the impact of RNF12 TOKAS variants on E3 activity, including variants within the RING domain and distal non-RING regulatory elements. Finally, we show that this technology can be rapidly deployed in human pluripotent stem cells. In summary, photoABPs are versatile tools that can directly identify disruptions to RING E3 ubiquitin ligase activity in human disease, thereby providing new insight into pathogenic mechanisms.
... feeding difficulties, microcephaly, epilepsy, brain MRI abnormalities, growth retardation and peculiar facial gestalt. [1][2][3][4][5][6][7][8][9] Wiedemann-Steiner syndrome (WSS, MIM#605130) is an autosomal dominant genetic syndrome caused by mutations in the KMT2A (Lysine methyltransferase 2A) gene located on chromosome 11 (11q23.3). ...
... In the DYRK1A syndrome, simple case reports or cohort analysis have highlighted the presence of ASD, attention deficit disorder with or without hyperactivity (ADHD), anxiety disorders and stereotyped behaviors, with variable frequencies. 1,4,[6][7][8][9]17 This is also the case in WSS, where descriptive studies have reported the presence of ASD, ADHD, anxiety disorders and aggressive behavior in individuals. 11,12,14,18 For both syndromes, individual behaviors described in the literature are rarely based on validated questionnaires and standardized tools. ...
DYRK1A and Wiedemann–Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient‐driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.
... Participants frequently struggled with sucking and swallowing in infancy and had a nasogastric (NGT) or gastrostomy tube (PEG/G-tubes) in situ as an infant (16/38). For four participants, feeding support with a G-tube continued into childhood (ID 6,14,21,30). Almost all had notable feeding difficulties, i.e., for overall motor abilities for feeding skills, measured by the ChOMPS, 12 participants were in the bottom 5th, and two individuals were at the 5th to 10th percentile, for their age. ...
Speech and language impairments are commonly reported in DYRK1A syndrome. Yet, speech and language abilities have not been systematically examined in a prospective cohort study. Speech, language, social behaviour, feeding, and non-verbal communication skills were assessed using standardised tools. The broader health and medical phenotype was documented using caregiver questionnaires, interviews and confirmation with medical records. 38 individuals with DYRK1A syndrome (23 male, median age 8 years 3 months, range 1 year 7 months to 25 years) were recruited. Moderate to severe intellectual disability (ID), autism spectrum disorder (ASD), vision, motor and feeding impairments were common, alongside epilepsy in a third of cases. Speech and language was disordered in all participants. Many acquired some degree of verbal communication, yet few (8/38) developed sufficient oral language skills to rely solely on verbal communication. Speech was characterised by severe apraxia and dysarthria in verbal participants, resulting in markedly poor intelligibility. Those with limited verbal language (30/38) used a combination of sign and graphic augmentative and alternative communication (AAC) systems. Language skills were low across expressive, receptive, and written domains. Most had impaired social behaviours (25/29). Restricted and repetitive interests were most impaired, whilst social motivation was a relative strength. Few individuals with DYRK1A syndrome use verbal speech as their sole means of communication, and hence, all individuals need early access to tailored, graphic AAC systems to support their communication. For those who develop verbal speech, targeted therapy for apraxia and dysarthria should be considered to improve intelligibility and, consequently, communication autonomy.
... Ce n'est qu'en 2008 que les premières mutations impliquant DYRK1A seul sont identifiées chez des patients avec microcéphalie (Møller et al., 2008 . D'autres mutations ponctuelles furent rapportées par la suite (Ji et al., 2015 ;Van Bon 40 2016 ; Luco et al., 2016). En parallèle, DYRK1A fut également considéré comme un gène impliqué dans les troubles du spectre autistique (TSA) suite à la découverte de mutations de novo lors des études de séquençage d'exome réalisées sur des cohortes de patients présentant des TSA (O'Roak et al., 2012, Iossifov et al., 2012Iossifov et al.,2014 ;Earl et al., 2017 (Courcet et al., 2012 ;O'Roak et al., 2012 ;Bronicki et al., 2015 ;Ruaud et al., 2015 ;Ji et al., 2015 ;van Bon et al., 2016 ;Luco et al., 2016 ;Earl et al., 2017 ;Blackburn et al., 2019 ;Lee et al., 2020 ;Meissner et al., 2020 ; (Earl et al., 2017). ...
... D'autres mutations ponctuelles furent rapportées par la suite (Ji et al., 2015 ;Van Bon 40 2016 ; Luco et al., 2016). En parallèle, DYRK1A fut également considéré comme un gène impliqué dans les troubles du spectre autistique (TSA) suite à la découverte de mutations de novo lors des études de séquençage d'exome réalisées sur des cohortes de patients présentant des TSA (O'Roak et al., 2012, Iossifov et al., 2012Iossifov et al.,2014 ;Earl et al., 2017 (Courcet et al., 2012 ;O'Roak et al., 2012 ;Bronicki et al., 2015 ;Ruaud et al., 2015 ;Ji et al., 2015 ;van Bon et al., 2016 ;Luco et al., 2016 ;Earl et al., 2017 ;Blackburn et al., 2019 ;Lee et al., 2020 ;Meissner et al., 2020 ; (Earl et al., 2017). Au niveau neurologique, des crises convulsives sont rapportées chez plus de la moitié des patients et des anomalies à l'IRM cérébrale peuvent également être mises en évidence (dilatation ou hypertrophie des ventricules, hypoplasie ou agénésie du corps calleux, retard de myélinisation de la substance blanche). ...
... Enfin, dans la plupart des cas on notera une dysmorphie faciale assez caractéristique avec entre autres : un oedème de la paupière supérieure, des yeux enfoncés, une lèvre supérieure fine ainsi qu'un rétrognathisme ( Figure 6). ( Møller et al., 2008 ;Van bon et al., 2011 ;Courcet et al., 2012 ;O'Roak et al., 2012 ;Redin et al., 2014 ;De Rubeis et al., 2014 ;Iglesias et al., 2014 ;Van Bon et al., 2016 ;Bronicki et al., 2015 ;Ruaud et al., 2015 ;Ji et al., 2015 ;Okamoto et al., 2015 ;Luco et al., 2016 ;Earl et al., 2017 ;Trujillano et al., 2017 ;Dang et al., 2018 ;Blackburn et al., 2019 ; la souris, l'embryon de poulet mais également dans le cerveau de patients atteints du SD (Guimera et al., 1996 ;Marti et al., 2003 ;Hämmerle et al., 2002 ;Wegiel et al., 2004). Un pic d'expression de Dyrk1a sera décrit dans le cerveau du rat à la naissance, suivi d'une diminution d'expression maintenue durant l'âge adulte (Okui et al., 1999). ...
La déficience intellectuelle (DI) est un trouble du neurodéveloppement et la première raison de consultation génétique. Cependant, un certain nombre de variants restent classés en tant que Variants de signification inconnue (VSI) et contribuent au phénomène d’errance diagnostique. De plus, la DI est caractérisée par une hétérogénéité génétique extrême et les mécanismes physiopathologiques associés sont généralement mal connues. Mon travail de doctorat a consisté à mettre au point des approches expérimentales permettant de reclasser l’ensemble des VSI dans les gènes DYRK1A et PQBP1. J’ai également investigué les mécanismes cellulaires dérégulés lors de l’inactivation de ces gènes dans un modèle de précurseurs neuronaux. Mes travaux de doctorat permettront donc d’améliorer le diagnostic moléculaire de la déficience intellectuelle associée à des mutations dans les gènes DYRK1A et PQBP1. Ils permettront également de mieux comprendre les mécanismes physiopathologiques impliqués dans ces troubles neurodéveloppementaux. Ces connaissances aideront à mieux prendre en charge les individus atteints et pourront permettre d’identifier de nouvelles cibles thérapeutiques.
... microdeletion syndrome associated to DYRK1A (ORPHA:268261) and intellectual deficit due to loss-of-function mutations in DYRK1A [4,5] (ORPHA:464311; also known as mental retardation, autosomal dominant disease 7: MRD7; OMIM #614104) show neurodevelopmental anomalies [4,[6][7][8][9][10], making this gene a critical dosage-sensitive gene for cognitive phenotypes. MRD7 is characterized by severe intellectual disability (ID), speech and motor delay, autism spectrum disorder (ASD), epileptic seizures and microcephaly [1,2,6,[10][11][12][13][14]. The rodent Dyrk1a is expressed in foetal and adult brains in dividing neuronal progenitors and later in the adult cerebellum, olfactory bulb and hippocampus [15][16][17][18]. ...
Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16 Lipi-Zbtb21 )1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.
... A recent study found that 48% and 81% of individuals with DYRK1A mutations exhibited ASD and ID, respectively (1). Primary microcephaly, described as decreased head circumference at birth (2)(3)(4), occurs in as many as 90% of these patients (1). Other clinical findings in this population include developmental delay, anxiety, seizures, speech and motor difficulties, and vision abnormalities (5,6). ...
... DYRK1A haploinsufficiency causes ASD, ID, and microcephaly in humans (4,5). Trisomy of chromosome 21 (including DYRK1A) causes Down syndrome and microcephaly (OMIM #190685). ...
... cHets also exhibited cortical thinning and enlarged ventricles, which may be explained by the excessive cell death observed. Interestingly, magnetic resonance imaging has revealed that patients with DYRK1A mutations also display enlarged ventricles and a hypoplastic corpus callosum (4). In addition to morphological aberrations, mouse models of Dyrk1a mutations have exhibited behavioral abnormalities, including altered social behavior (14,15,46,47), and our finding of altered social interest in cHets illustrated the necessity of Dyrk1a in the cortex for encoding this behavior. ...
Background
Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood.
Methods
We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations.
Results
We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B–brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-1), both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants.
Conclusions
Altogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place DYRK1A as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies.
