Recurrent mutations in the DYRK1A gene have been identified in multiple individuals with ASD as described below. A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified DYRK1A as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD in van Bon et al., 2016 identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Furthermore, phenotypic comparison of 15 cases with DYRK1A disruptions in this report identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features (PMID 28053047). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified DYRK1A as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104].
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References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Transgenic mice were generated using Dyrk1A full length cDNA into male pronuclei. The cDNA is under the sheep promoter for metallothione IA.
Allele Type: Transgenic
Strain of Origin: C57BL6/SJL
Genetic Background: C57BL6/SJL
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A targeting vector was constructed with homology (5') to 3.6 kb of exon 6 and 2.1 kb of exon 8 (3'), containing PGKneobpA cassette and PGKtk cassette. This construct was linearized and electroporated into E14.1 cells.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6*129
ES Cell Line: E14.1
Mutant ES Cell Line: Model Source: Maria Arbones lab (PMID 12192061)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A targeting vector was constructed with homology (5') to 3.6 kb of exon 6 and 2.1 kb of exon 8 (3'), containing PGKneobpA cassette and PGKtk cassette. This construct was linearized and electroporated into E14.1 cells.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6*129
ES Cell Line: E14.1
Mutant ES Cell Line: Model Source: Maria Arbones lab (PMID 12192061)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous Dyrk1a mice were generated by breeding female EIIa-Cre (MGI:2137691) mice, with germ-line Cre recombinase expression, with male Dyrk1a^f/+ mice (MGI:5648391).
Allele Type: Knockout
Strain of Origin: FVB/N; C57BL/6NTac
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source: Laboratory of Mammalian Genes and Development, Heiner Westphal; John D Crispino
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Lentiviruses expressing Cre-GFP under the control of CaMKIIalpha promoter were injected into the dentate gyrus of adult Dyrk1a^f/f mice (MGI:5648391) to delete both alleles of Dyrk1a in DGCs.
Allele Type: Conditional knockout
Strain of Origin: C57BL/6NTac
Genetic Background: ES Cell Line: PRX-B6N
Mutant ES Cell Line: Model Source: John D Crispino
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Lentiviruses expressing Cre-GFP under the control of CaMKIIalpha promoter were injected into the dentate gyrus of adult Dyrk1a^f/+ (MGI:5648391) to delete one allele of Dyrk1a in DGCs.
Allele Type: Conditional knockout
Strain of Origin: C57BL/6NTac
Genetic Background: ES Cell Line: PRX-B6N
Mutant ES Cell Line: Model Source: John D Crispino
Description: Retardation in neuromotor development were observed: persistence of immature locomotor pattern, delayed maturation of gait. increased turnings at p10 compared to littermate controls. increased latency to reach the goal arena.
Exp Paradigm: Pivoting test: observed number of turnings. gait- observerd initiation of walking activity. homing test- observed movement towards a goal areana containing home cage nest material ( in a cage where 2/3 is new material and 1/3rd is the home nest mateiral)- gait
Description: Increased number of crossings in the periphery and center of arena. increased number of entries in open and closed arms of plus maze
Exp Paradigm: Elevated plus maze test
Description: Reduction in latency to fall in the wire suspension test compared to control littermates
Exp Paradigm: Latency for falling for falling down is measured
Description: Retardation in neuromotor development were observed: persistence of immature locomotor pattern, delayed maturation of gait. increased turnings at p10 compared to littermate controls. increased latency to reach the goal arena.
Exp Paradigm: Pivoting test: observed number of turnings. gait- observerd initiation of walking activity. homing test- observed movement towards a goal areana containing home cage nest material ( in a cage where 2/3 is new material and 1/3rd is the home nest mateiral)-pivoting test
Description: Reduction in latency to fall in the wire suspension test compared to control littermates
Exp Paradigm: Latency for falling for falling down is measured
Description: Retardation in neuromotor development were observed: persistence of immature locomotor pattern, delayed maturation of gait. increased turnings at p10 compared to littermate controls. increased latency to reach the goal arena.
Exp Paradigm: Pivoting test: observed number of turnings. gait- observerd initiation of walking activity. homing test- observed movement towards a goal areana containing home cage nest material ( in a cage where 2/3 is new material and 1/3rd is the home nest mateiral)- homing test
Description: Increased number of crossings in the periphery and center of arena. increased number of entries in open and closed arms of plus maze
Exp Paradigm: Open field test
Description: In the probe test, transgenic dyrk1a mice displayed reduced memory of the placement of the platform, compared to controls.
Exp Paradigm: NA
Description: Transgenic dyrk1a mice show increase in average escape latencies and distance traveled compared to compared to controls in the odd trials ( where the position of the platform is changed from the even or first trial)- indicating problems in reference memory and flexibility. but not in working memory
Exp Paradigm: More cognitively demanding than the first phase of the morris water maze, further training to repeated reversal learning where the platform is placed in a different quadrant in two consecutive- paired trials each-over eight sessions, one session each day.
Description: Significant growth delay, with 1/3 - 1/2nd size reduction compared to wildtype littermate, during embryonic development
Exp Paradigm: Morphology analyzed by cresyl violet staining
Description: There is a significant delay in the appearance of righting reflex in the hets compared to controls
Exp Paradigm: The reflex evaluates the ability of animals to turn from a supine to a prone position.
Description: Mutants show increase in the number of neurons born on e13.5 in the somatosensory cortex compared with controls indicating increased neuron production during early and mid-corticogenesis. mutants show no change in the number of neurons in the neocortex born at e15.5 or e17.5 compared with controls, indicating neurogenesis ends at the correct developmental timepoint.
Exp Paradigm: Brdu birth dating assay; brdu labeling at e13.5 and e15.5
Description: Mutants show increase in the number of neurons in the cortical layers and increased neuronal density in the cortical layers compared with controls.
Exp Paradigm: Cerebral cortex
Description: Dyrk1a heterozygous mice at P5 show a similar distribution of GFAP-positive cells (astrocytes) to that in the controls in the neocortex but with significantly more cells. Astrocytes were also more abundant in mutant neocortices at P7 and they were more widespread across the cortical plate than in control animals.
Exp Paradigm: GFAP
Description: At P19, mutant axons had a smaller caliber and their myelin sheaths were slightly thicker than those around the control axons (smaller g-ratios: axon diameter/fiber diameter).
Description: There was a significantly lower percentage of OLIG2-positive cells (marker for oligodendrocytes and oligodendrocyte precursor cells) in Dyrk1a heterozygous brain at E17.5 and P0. There was a significant reduction of OLIG2-positive cells at P7 in the corpus callosum. At E15.5, the mantel zone of the Dyrk1a heterozygous lateral ganglionic eminence (LGE) contained fewer OLIG2-positive cells and fewer cells double labelled OLIG2-positive and PDGFRalpha-positive (a marker for oligodendrocyte precursors cells) than in controls. At E17.5, the Dyrk1a heterozygote dorsal telencephalon had fewer OLIG2-positive and double labelled OLIG2-positive and PDGFRalpha-positive cells in the germinal region than the controls, as well as fewer OLIG2-positive cells in the interm
Exp Paradigm: OLIG2, PDGFRalpha, CC1, MBP
Description: Dyrk1a heterozygous mice embryos had a greater amount of SOX2-positive cells in the dorsal germinal region compared to wildtype control embryos, indicating an accumulation of neural progenitors at the end of the neurogenic period.
Exp Paradigm: SOX2
Description: Dyrk1a heterozygous cerebral cortices had SOX9-positive cells (adult brain astrocytes outside neurogenic regions) that were distributed similarly through all layers, but were more abundant compared to wildtype controls. A similar increase in SOX9-positive cells was observed in the heterozygous Dyrk1a hippocampi.
Exp Paradigm: SOX9
Description: Mutants show an increase in the number of gaba positive inhibitory neurons in the internal but not the external layers of the neocortex compared with controls.
Exp Paradigm: Neocortex
Description: The brains of adult hets were about 30% smaller than those of wild type mice. a significant reduction was seen in the mesencephalic tectum (superior and inferior colliculi.
Exp Paradigm: NA
Description: Mutants show decrease in the thickness of neocortical layers compared with controls.
Exp Paradigm: Counted the number of neurons that express the neuronal marker neun in the internal (v-vi) and external (ii-iv) layers of the somatosensory cortex (ssc) at p7
Description: Mutants show increase in excitatory neurons (neun positive and gaba negative) in the internal and external layers of the neocortex compared with controls.
Exp Paradigm: Neocortex
Description: Reductions in midbrain and hindbrain regions, cerebral cortex and olfactory bulb. ventral brain regions, hypothalamus, pons and medulla oblongata were more severaly affected than dorsal structures. no obvious malformations were observed.
Exp Paradigm: NA
Description: At 2 months, no differences in callosal axon node densities were observed between Dyrk1a heterozygous and control mice, however, axonal regions immunolabeled for NAV1.6 were shorter in Dyrk1a heterozygous mice, and their labelling was significantly weaker.
Exp Paradigm: NAV1.6, CASPR
Description: Mutants show an increase in the number of vglut1 positive excitatory synapses in layers iv and vi compared with controls.
Exp Paradigm: Neocortex
Description: At 2 months, conduction velocities arising from myelinated and unmyelinated axons were significantly slower in Dyrk1a heterozygote mutants, although greater differences between the genotypes were evident in continuous rather than in saltatory conduction. At 12 months, continuous and saltatory conduction velocities were slower in Dyrk1a heterozygous mice.
Description: Mutants spent more time in repetitive digging compared with controls in presence of the intruder mouse.
Exp Paradigm: Oral-oral or oral-genital sniffing frequencies were measured
Electroencephalogram (eeg): signature of seizure/epilepsy2
Increased
Description: Mutants show decreased basal electrical activity in the brain, increased spontaneous myoclonic jerks with corresponding eleptiform interictal activity, increase in isolated spikes, polyspikes and spike wave discharges, increased episodes of immobility characterized by spikes and polyspikes, and increased incidence of handling-induced seizures, compared with controls.
Exp Paradigm: NA
Description: Mutants sniff an unfamiliar same sex social stimulus intruder mouse fewer times than controls.
Exp Paradigm: Oral-oral or oral-genital sniffing frequencies were measured
Description: Mutant pups show decrease in the duration of usv calls compared with controls when separated from their mothers. mutants show no change in the number of usv calls compared with controls when separated from their mothers.
Exp Paradigm: NA
Description: In the gestational period, the pups appeared normal. however the adults were dinstinctly smaller, with reduced body weight and length. the cerebellum and liver were disproportionately reduced in weight.
Exp Paradigm: Morphology analyzed by cresyl violet staining
Description: 29% of the live born pups died within 3 days of life, 30% reduction in number of hets compared to the expected mendelian ratio
Exp Paradigm: Wild type dyrk1a mice wer crossed with dyrk1a+/- to produce progeny
Genotypic ratio of progeny from heterozygous parents
Description: Mutants spent less time exploring the central region of the arena during the marble burying test compared with controls.
Exp Paradigm: 20 min assay
Description: Mutants show increase in the transcript levels of notch2, sox4, sox11 and nfi1b genes involved in glial development compared with controls.
Exp Paradigm: Cerebral cortex
Description: Mutants show decreased expression of some of the genes that were up-regulated during development in controls and vice versa whereas many differentiatially expressed genes were changed in the same direction in mutants as in controls, indicating dyrk1a haploinsufficiency does not have a strong impact on transcriptional regulation during corticogenesis but may affect the timecourse of transcriptional regulation.
Exp Paradigm: Cerebral cortex
Description: Mutants show decrease in penk, htr7 and gabrg1 involved in synaptic transmission and decrease in nefl and nefm involved in axon growth compared with controls.
Exp Paradigm: Cerebral cortex
Description: At 2 months, the cerebral cortex of Dyrk1a heterozygous mutants showed similar levels of MBP but twice as much PLP than the controls, two major myelin-associated proteins in the central nervous system.
Exp Paradigm: MBP, PLP
Description: Dyrk1a mutant mice exhibited a decrease in the number of VGlut1+ MFT filopodial contacts with PV INs compared to wildtype controls.
Exp Paradigm: VGlut1
Description: Dyrk1a mutant mice exhibited a decrease in PV puncta (perisomatic synaptic contacts) density in CA3 neurons compared to wildtype controls.
Exp Paradigm: PV
Description: Dyrk1a mutant mice exhibited a significant decrease in PV IN perisomatic contacts in the CA2 subregion compared to controls.
Exp Paradigm: PV
Miniature post synaptic current frequency: inhibitory1
Decreased
Description: Dyrk1a mutant mice exhibited a significant decrease in the frequency of miniature inhibitory post synaptic currents compared to wildtype controls.
Exp Paradigm: CA3 pyramidal neuron
Description: Dyrk1a mutant mice exhibited reduced excitability, as measured by the number of actional potential spikes, compared to controls.
Exp Paradigm: Optogenetics; CA3 pyramidal neuron
Miniature post synaptic current frequency: inhibitory1
Decreased
Description: Dyrk1a mutant mice exhibited a significant decrease in the frequency of miniature inhibitory post synaptic currents compared to wildtype controls.
Exp Paradigm: CA2 pyramidal neuron
Description: Dyrk1a mutant mice exhibited reduced excitability, as measured by the number of actional potential spikes, compared to controls.
Exp Paradigm: Optogenetics; CA2 pyramidal neuron
Description: Dyrk1a mutant mice exhibited a significant increase in the amplitude of excitatory post synaptic currents compared to wildtype controls.
Exp Paradigm: Optogenetics; CA3 pyramidal neuron
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Dyrk1a mutant mice exhibited a significant decrease in the frequency of miniature excitatory post synaptic currents compared to wildtype controls.
Exp Paradigm: hippocampal mossy fiber-parvalbumin interneuron
Description: Dyrk1a mutant mice exhibited a significant increase in the amplitude of excitatory post synaptic currents compared to wildtype controls.
Exp Paradigm: Optogenetics; CA2 pyramidal neuron
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Dyrk1a mutant mice exhibited a significant decrease in the frequency of miniature excitatory post synaptic currents compared to wildtype controls.
Exp Paradigm: CA3 hippocampal mossy fiber-parvalbumin interneurons
Description: Dyrk1a mutant mice exhibited no preference for a stranger mouse, spending less time interacting with a stranger mouse over an empty cup compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s1), empty cup in chamber 2
Description: Dyrk1a mutant mice exhibited an approximately 50% reduction in Dryk1a expression in the DG, CA2/CA3, sensorimotor cortex, and hypothalamus.
Description: Dyrk1a mutant mice exhibited no decrease in Ablim3 levels in mossy fiber terminals following social experience, while in controls, these levels decreased significantly.
Exp Paradigm: Reciprocal social interaction test
Description: Dyrk1a mutant mice exhibited a decrease in the number of VGlut1+ MFT filopodial contacts with PV INs compared to wildtype controls.
Exp Paradigm: VGlut1
Description: Dyrk1a mutant mice exhibited a decrease in PV puncta (perisomatic synaptic contacts) density in CA3 neurons compared to wildtype controls.
Exp Paradigm: PV
Description: Dyrk1a mutant mice spent less time interacting with a stranger mouse over an empty cup compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s1), empty cup in chamber 2
Description: Dyrk1a mutant mice exhibited no preference for a stranger mouse, spending less time interacting with a stranger mouse over an empty cup compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s1), empty cup in chamber 2
Description: Dyrk1a mutant mice exhibited a decrease in the number of VGlut1+ MFT filopodial contacts with PV INs compared to wildtype controls.
Exp Paradigm: VGlut1
Description: Dyrk1a mutant mice exhibited a decrease in PV puncta (perisomatic synaptic contacts) density in CA3 neurons compared to wildtype controls.
Exp Paradigm: PV
Description: Dyrk1a mutant mice exhibited no preference for a stranger mouse, spending less time interacting with a stranger mouse over an empty cup compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s1), empty cup in chamber 2
