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FLASH GENE

Symbol

DYRK1A

contributors: mct/pg/shn - updated : 16-12-2014

HGNC name	dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A
HGNC id	3091

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DEL21QD chromosome 21q deletion, including the APP-SOD1 region MRD7 mental retardation, autosomal dominant 7 TRI21 trisomy 21
Location	21q22.13      Physical location : 38.739.858 - 38.887.678
Synonym name	dual specificity YAK1-related kinase
	dual specificity tyrosine-phosphorylation-regulated kinase 1A
	minibrain (Drosophila) homolog
	protein kinase minibrain homolog
	serine/threonine kinase MNB
	serine/threonine-specific protein kinase
	mnb protein kinase homolog hp86
	MNB/DYRK protein kinase
	dual-specificity tyrosine-Y-phosphorylation regulated kinase, EC 2.7.19
Synonym symbol(s)	MNB, MNBH, DYRK1, DYRK, HP86, MRD7
EC.number	2.7.12.1

DNA

TYPE	functioning gene
STRUCTURE	95.08 kb     13 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   HRE
text structure	REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp &
	8722;833 to &
	8722;815 of the promoter

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D21S1900 - D21S1919 - DYRK1A - D21S1917 - D21S259 - qter
Authors	PMID: 10329007

regionally located

located in the Down syndrome critical region (DCR)

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001396 11 splicing 5212 NP_567824 85.5 763 - 1999 10329007 NM_001395 13 splicing 5517 NP_567824 66 584 - 1999 10329007 being alternatively spliced in the 5' region and in the 3' part of the coding region compared to variant 1 lacking the poly-His domain MNBH, isoform 1, 2, 3, 4 differing by C termini NM_130436 11 splicing 6580 NP_569120 84.4 754 - 1999 10329007 being alternatively spliced in the 5' region and in an internal region of the coding sequence compared to variant 1 NM_130438 10 splicing 5088 NP_569122 60.2 529 - 1999 10329007 lacking a 3' coding exon compared to variant 1 lacking the poly-His domain

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Homo sapiens Digestive intestine large intestine colon   highly Homo sapiens   liver       lowly Mus musculus   liver       moderately Homo sapiens Endocrine adrenal gland       lowly Mus musculus   pancreas       lowly Homo sapiens Nervous brain diencephalon amygdala   highly Homo sapiens   brain midbrain substantia nigra   lowly Homo sapiens   brain forebrain cerebral cortex   moderately Homo sapiens   brain basal nuclei corpus callosum   moderately Homo sapiens   brain       highly Homo sapiens Reproductive female system breast     lowly Homo sapiens Respiratory lung       lowly Mus musculus   lung       moderately Homo sapiens Urinary kidney       highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum     highly Mus musculus

cells

System Cell Pubmed Species Stage Rna symbol Skin/Tegument keratinocyte Homo sapiens

cell lineage
cell lines
fluid/secretion	blood

at STAGE

physiological period

embryo, fetal

Text	brain, liver, lung, heart

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal domain, but not the catalytic kinase domain or the C-terminal domain of DYRK1A, was responsible for the WDR68 binding
	nuclear targeting sequence
	a putative leucine zipper motif
	a conserved histidine repeat (13 residues)

conjugated

PhosphoP

HOMOLOGY

interspecies	ortholog to Dyrk1a, Rattus norvegicus
	ortholog to Dyrk1a, Mus musculus
	ortholog to DYRK1A, Pan troglodytes
	ortholog to dyrk1a, Danio rerio

Homologene

FAMILY	protein kinase superfamily
	Ser/Thr protein kinase family
	MNB/DYRK subfamily

CATEGORY

enzyme , regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
text	coexpressed with Notch in various tissues during embryonic development
	predominantly localized to the nucleus

basic FUNCTION	serine/threonine and tyrosine kinase involved in post-embryonic neurogenesis
	putatively involved in cell growth and development
	playing a role in controlling motor function and may be implicated in Down syndrome motor dysfunction
	involved in the signaling mechanisms that regulate dendrite differentiation
	involved with RCAN1 in the cooperative destabilization of a regulatory circuit, leading to reduced NFATc activity
	may play a role in a signaling pathway regulating nuclear functions of cell proliferaration
	could be responsible for learning and memory deterioration in Down syndrome and of memory impairment in ALzheimer disease
	playing a physiological role in the hyperphosphorylation of Tau responsible of insoluble deposits in Alzheimer disease
	playing an important, but diverse from developmental role in adult central nervous system
	inhibiting the expression of REST(a key regulator of pluripotency and neuronal differentiation), an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain (deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages)
	negative regulator of the intrinsic apoptotic pathway in the developing retina (phosphorylates caspase-9 on threonine residue 125, and this phosphorylation event is crucial to protect retina cells from apoptotic cell death)
	positively regulates FGF-mitogen-activated protein kinase signaling by phosphorylation-dependent impairment of the inhibitory activity of SPRY2
	might modulate the hypertrophic response of cardiomyocytes
	promotes cell survival through phosphorylation and activation of SIRT1 with DYRK3
	role in controlling synaptic vesicle recycling processes
	role of DYRK1A in the regulation of neurite formation
	DYRK1A, DYRK2, and DYRK4 phosphorylate distinct although overlapping sets of the 720 different peptides in the phosphosite array
	DYRK1A and REST are closely related in neurodevelopment
	DYRK1A, DYRK3, DYRK4 implicated in the regulation of cytoskeletal organization and process outgrowth in neurons
	plays a role in many cellular pathways through phosphorylation of diverse substrate proteins
	DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing CCND3

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

autophosphorylated

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	cyclin L2
	14-3-3 protein
	phytanoyl-CoA alpha-hydroxylase associated protein 1, PAHX-AP1
	SF3B1
	SPRY2
	REST/NRSF-SWI/SNF chromatin remodelling complex
	dynamin 1, endophilin 1
	SPRED1 and SPRED2
	DCAF7
	DYRK1A binds specifically to DCAF7 in cells, and the binding, but not the phosphorylation event, induces the nuclear translocation of DCAF7 5)
	RCAN1
	DYRK1A interacts with and phosphorylates STXBP1 at the Thr(479) residue,linking STXBP1 and DYRK1A in synaptic vesicle trafficking and amyloid precursor protein processing
	DYRK1A restrains CCND3 protein levels by phosphorylating T283 to induce its degradation
	DYRK1A may also down-regulate CIC in human cells

cell & other

REGULATION

inhibited by

RANBP9

repressed by

TFAP4/GMNN complex

ASSOCIATED DISORDERS

corresponding disease(s)

TRI21 , DEL21QD , MRD7

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   significantly elevated in hippocampus of patients with Alzheimer constitutional   deletion     haploinsufficiency causative for microcephaly observed in partial monosomy 21 constitutional     --other   DYRK1A dosage imbalance perturbs REST levels with decreased REST expression in embryonic neurons and increased expression in adult neurons constitutional     --over   contributes to neurofibrillary degeneration in Down syndrome more significantly than in subjects with two copies of the DYRK1A gene and sporadic Alzheimer disease) constitutional     --over   as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of MAPT exon 10 to an increase in the ratio of 3R-tau/4R-tau

Susceptibility

Variant & Polymorphism

Candidate gene	for mental retardation in Down syndrome through deregulation of REST
Marker
Therapy target	normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment
	System Type Disorder Pubmed mental retardation trisomy   DYRK1A inhibitor has been proposed as a novel drug to address learning and memory deficit in Down syndrome

ANIMAL & CELL MODELS

	Dyrk1A Mutant Drosophila minibrain flies have a reduction in both optic lobes and central brain, showing learning deficits and hypoactivity
	mice overexpressing the full-length cDNA of Dyrk1A exhibit delayed cranio-caudal maturation with functional consequences in neuromotor development, altered motor skill acquisition and hyperactivity, a significant impairment in spatial learning and cognitive flexibility, hippocampal and prefrontal cortex dysfunction
	Dyrk1A(-/-) mice have a general growth delay and die during midgestation and Dyrk1A(+/-) mice show decreased neonatal viability and a significant body size reduction from birth to adulthood
	Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity
	increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein