{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:15:18Z","timestamp":1791396918630,"version":"4.3.3"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p><jats:italic>DYRK1A<\/jats:italic> syndrome results from a reduction in copy number of the <jats:italic>DYRK1A<\/jats:italic> gene, which resides on human chromosome 21 (Hsa21). <jats:italic>DYRK1A<\/jats:italic> has been implicated in the development of cognitive phenotypes associated with many genetic disorders, including Down syndrome (DS) and Alzheimer\u2019s disease (AD). Additionally, overexpression of <jats:italic>DYRK1A<\/jats:italic> in DS has been implicated in the development of abnormal skeletal phenotypes in these individuals. Analyses of mouse models with <jats:italic>Dyrk1a<\/jats:italic> dosage imbalance (overexpression and underexpression) show skeletal deficits and abnormalities. Normalization of <jats:italic>Dyrk1a<\/jats:italic> copy number in an otherwise trisomic animal rescues some skeletal health parameters, and reduction of <jats:italic>Dyrk1a<\/jats:italic> copy number in an otherwise euploid (control) animal results in altered skeletal health measurements, including reduced bone mineral density (BMD) in the femur, mandible, and skull. However, little research has been conducted thus far on the implications of <jats:italic>DYRK1A<\/jats:italic> reduction on human skeletal health, specifically in individuals with <jats:italic>DYRK1A<\/jats:italic> syndrome. This review highlights the skeletal phenotypes of individuals with <jats:italic>DYRK1A<\/jats:italic> syndrome, as well as in murine models with reduced <jats:italic>Dyrk1a<\/jats:italic> copy number, and provides potential pathways altered by a reduction of <jats:italic>DYRK1A<\/jats:italic> copy number, which may impact skeletal health and phenotypes in these individuals. Understanding how decreased expression of <jats:italic>DYRK1A<\/jats:italic> in individuals with <jats:italic>DYRK1A<\/jats:italic> syndrome impacts bone health may increase awareness of skeletal traits and assist in the development of therapies to improve quality of life for these individuals.<\/jats:p>","DOI":"10.3389\/fnins.2024.1462893","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T11:34:12Z","timestamp":1725622452000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Skeletal health in DYRK1A syndrome"],"prefix":"10.3389","volume":"18","author":[{"given":"Elysabeth D.","family":"Otte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall J.","family":"Roper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1002\/mnfr.201500781","article-title":"Differential effects of Epigallocatechin-3-gallate containing supplements on correcting skeletal defects in a down syndrome mouse model","volume":"60","author":"Abeysekera","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1091\/mbc.e06-08-0668","article-title":"DYRK1A autophosphorylation on serine residue 520 modulates its kinase activity via 14-3-3 binding","volume":"18","author":"Alvarez","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1007\/s003300050726","article-title":"Bone mineral density in adults with Down's syndrome","volume":"9","author":"Angelopoulou","year":"1999","journal-title":"Eur. Radiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","article-title":"Down syndrome","volume":"6","author":"Antonarakis","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.pharmthera.2018.09.010","article-title":"DYRK1A and cognition: a lifelong relationship","volume":"194","author":"Arbones","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e2575","DOI":"10.1371\/journal.pone.0002575","article-title":"Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A)","volume":"3","author":"Arque","year":"2008","journal-title":"PLoS One"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.nbd.2019.02.022","article-title":"Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome","volume":"127","author":"Arranz","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nature04678","article-title":"NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21","volume":"441","author":"Arron","year":"2006","journal-title":"Nature"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e1289","DOI":"10.1038\/cddis.2014.253","article-title":"DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease","volume":"5","author":"Barallobre","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.nbd.2005.02.004","article-title":"Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+\/\u2212 mouse","volume":"20","author":"Benavides-Piccione","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"5687","DOI":"10.1093\/hmg\/ddv284","article-title":"Rescue of the abnormal skeletal phenotype in Ts65Dn down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a","volume":"24","author":"Blazek","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41413-017-0004-5","article-title":"mTOR signaling in skeletal development and disease","volume":"6","author":"Chen","year":"2018","journal-title":"Bone Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1754-4505.2008.00020.x","article-title":"Skeletal age of individuals with down syndrome","volume":"28","author":"de Moraes","year":"2008","journal-title":"Spec. Care Dentist."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"9355","DOI":"10.3390\/ijms23169355","article-title":"The omnipresence of DYRK1A in human diseases","volume":"23","author":"Deboever","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S1079-2104(97)90343-7","article-title":"Down syndrome: a review of the literature","volume":"84","author":"Desai","year":"1997","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13229-017-0173-5","article-title":"Clinical phenotype of ASD-associated DYRK1A haploinsufficiency","volume":"8","author":"Earl","year":"2017","journal-title":"Mol. Autism."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"6636","DOI":"10.1128\/MCB.22.18.6636-6647.2002","article-title":"Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice","volume":"22","author":"Fotaki","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1037\/0735-7044.118.4.815","article-title":"Haploinsufficiency of Dyrk1A in mice leads to specific alterations in the development and regulation of motor activity","volume":"118","author":"Fotaki","year":"2004","journal-title":"Behav. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.tice.2018.10.002","article-title":"Dyrk1A promotes the proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via down-regulating Spry2 and activating the ERK MAPK pathway","volume":"55","author":"Guo","year":"2018","journal-title":"Tissue Cell"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1290949","DOI":"10.3389\/fgene.2023.1290949","article-title":"Identification of two novel and one rare mutation in DYRK1A and prenatal diagnoses in three Chinese families with intellectual Disability-7","volume":"14","author":"Huang","year":"2023","journal-title":"Front. Genet."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e0264254","DOI":"10.1371\/journal.pone.0264254","article-title":"Increased dosage and treatment time of Epigallocatechin-3-gallate (EGCG) negatively affects skeletal parameters in normal mice and down syndrome mouse models","volume":"17","author":"Jamal","year":"2022","journal-title":"PLoS One"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1038\/ejhg.2015.71","article-title":"DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies","volume":"23","author":"Ji","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref23","first-page":"63","article-title":"Dyrk1a is required for craniofacial development in Xenopus laevis","volume-title":"Dev. Biol","author":"Johnson","year":"2024"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e78069","DOI":"10.7554\/eLife.78069","article-title":"Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway","author":"Kim","year":"2022","journal-title":"eLife"},{"key":"ref25","doi-asserted-by":"crossref","DOI":"10.1242\/dmm.050914","volume-title":"Sex specific emergence of trisomic Dyrk1a-related skeletal phenotypes in the development of a down syndrome mouse model","author":"LaCombe","year":"2024"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s00018-020-03626-4","article-title":"DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis","volume":"78","author":"Laham","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"117046","DOI":"10.1016\/j.bone.2024.117046","article-title":"Compromised femoral and lumbovertebral bone in the Dp(16)1Yey down syndrome mouse model","volume":"181","author":"Lamantia","year":"2024","journal-title":"Bone"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"eadd6883","DOI":"10.1126\/scitranslmed.add6883","article-title":"Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of down syndrome","volume":"16","author":"Lana-Elola","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/ajmg.a.63412","article-title":"Growth charts in DYRK1A syndrome","volume":"194","author":"Lanvin","year":"2024","journal-title":"Am. J. Med. Genet. A"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"33343","DOI":"10.1074\/jbc.M109.042234","article-title":"Negative feedback inhibition of NFATc1 by DYRK1A regulates bone homeostasis","volume":"284","author":"Lee","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1093\/hmg\/ddp047","article-title":"DYRK1A interacts with the REST\/NRSF-SWI\/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of down syndrome","volume":"18","author":"Lepagnol-Bestel","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1002\/jcb.25148","article-title":"RE1-silencing transcription factor (Rest) is a novel regulator of osteoblast differentiation","volume":"116","author":"Liu","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1007\/s10753-023-01813-6","article-title":"Deletion of DYRK1A accelerates osteoarthritis progression through suppression of EGFR-ERK signaling","volume":"46","author":"Liu","year":"2023","journal-title":"Inflammation"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1111\/j.1601-183X.2006.00285.x","article-title":"Dopaminergic deficiency in mice with reduced levels of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A, Dyrk1A(+\/\u2212)","volume":"6","author":"Martinez de Lagran","year":"2007","journal-title":"Genes Brain Behav."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"4856","DOI":"10.1093\/hmg\/ddw309","article-title":"Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with down syndrome","volume":"25","author":"McElyea","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e1544","DOI":"10.1002\/mgg3.1544","article-title":"DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature","volume":"8","author":"Meissner","year":"2020","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.ebiom.2015.01.010","article-title":"DYRK1A-mediated cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in down syndrome","volume":"2","author":"Najas","year":"2015","journal-title":"EBioMedicine"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.neuron.2016.03.027","article-title":"Phosphorylation of beta-tubulin by the down syndrome kinase, Minibrain\/DYRK1a, regulates microtubule dynamics and dendrite morphogenesis","volume":"90","author":"Ori-McKenney","year":"2016","journal-title":"Neuron"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"244","DOI":"10.5607\/en.2013.22.4.244","article-title":"New perspectives of Dyrk1A role in neurogenesis and Neuropathologic features of down syndrome","volume":"22","author":"Park","year":"2013","journal-title":"Exp. Neurobiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"19912","DOI":"10.1038\/s41598-022-24284-5","article-title":"Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome","volume":"12","author":"Pijuan","year":"2022","journal-title":"Sci. Rep."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1038\/s41388-022-02245-6","article-title":"The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target","volume":"41","author":"Rammohan","year":"2022","journal-title":"Oncogene"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1001\/archpedi.1966.02090150110012","article-title":"Long bone growth in Down's syndrome","volume":"112","author":"Rarick","year":"1966","journal-title":"Am. J. Dis. Child."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.nbd.2017.12.003","article-title":"DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures","volume":"110","author":"Raveau","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"dev201077","DOI":"10.1242\/dev.201077","article-title":"Craniofacial dysmorphology in down syndrome is caused by increased dosage of Dyrk1a and at least three other genes","volume":"150","author":"Redhead","year":"2023","journal-title":"Development"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1002\/(SICI)1097-0177(200002)217:2<137::AID-DVDY1>3.0.CO;2-N","article-title":"Parallels of craniofacial maldevelopment in down syndrome and Ts65Dn mice","volume":"217","author":"Richtsmeier","year":"2000","journal-title":"Dev. Dyn."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"dmm049927","DOI":"10.1242\/dmm.049927","article-title":"Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in down syndrome model mice","volume":"16","author":"Sloan","year":"2023","journal-title":"Dis. Model. Mech."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e67470","DOI":"10.1371\/journal.pone.0067470","article-title":"NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin\/NFAT pathway and the down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect","volume":"8","author":"Stefos","year":"2013","journal-title":"PLoS One"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/mgg3.334","article-title":"Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve down syndrome deficits","volume":"5","author":"Stringer","year":"2017","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1007\/s11914-021-00674-y","article-title":"Current analysis of skeletal phenotypes in down syndrome","volume":"19","author":"Thomas","year":"2021","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.3390\/genes12111729","article-title":"Skeletal deficits in male and female down syndrome model mice Arise independent of normalized Dyrk1a expression in osteoblasts","volume":"12","author":"Thomas","year":"2021","journal-title":"Genes (Basel)"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"E3632","DOI":"10.1073\/pnas.1701054114","article-title":"NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice","volume":"114","author":"Tomlinson","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/S0022-3476(05)82068-2","article-title":"Treatment of children with down syndrome and growth retardation with recombinant human growth hormone","volume":"119","author":"Torrado","year":"1991","journal-title":"J. Pediatr."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.ejmg.2012.03.011","article-title":"Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy","volume":"55","author":"Valetto","year":"2012","journal-title":"Eur. J. Med. Genet."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/mp.2015.5","article-title":"Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID","volume":"21","author":"van Bon","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref55","volume-title":"DYRK1A syndrome in GeneReviews\u00ae [Internet]","author":"van Bon","year":"2015"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"e64872","DOI":"10.7554\/eLife.64872","article-title":"7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis","volume":"10","author":"Xue","year":"2021","journal-title":"eLife"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1080\/14767058.2018.1511695","article-title":"The role of fetal growth restriction in the association between down syndrome and perinatal mortality","volume":"33","author":"Yao","year":"2020","journal-title":"J. Matern. 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