DYRK1A explained

Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the DYRK1A gene.^[1] Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region.^[2] These variants encode for at least five different isoforms.^[3]

Function

See also: Dual-specificity kinase. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of the Drosophila mnb (minibrain) gene.

DYRK1A has also been shown to modulate plasma homocysteine levels in a mouse model of overexpression.^[4]

Clinical significance

DYRK1A 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.^[3] In addition, a polymorphism (SNP) in DYRK1A was found to be associated with HIV-1 replication in monocyte-derived macrophages, as well as with slower progression to AIDS in two independent cohorts of HIV-1-infected individuals.^[2] Mutations in DYRK1A are also associated with autism spectrum disorder.^{[5] [6]}

Interactions

DYRK1A has been shown to interact with WDR68.^[7]

In popular culture

Rosie, the learning-disabled protagonist of BBC sitcom There She Goes, has DYRK1A syndrome, as revealed in the show's final episode.^[8]

See also

• DYRK1B
• DYRK2
• DYRK3

Further reading

• Hämmerle B, Elizalde C, Galceran J, Becker W, Tejedor FJ . The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications . Journal of Neural Transmission. Supplementum . 67 . 129–137 . 2004 . 15068245 . 10.1007/978-3-7091-6721-2_11 . 978-3-211-40776-9 .
• Galceran J, de Graaf K, Tejedor FJ, Becker W . The MNB/DYRK1A protein kinase: genetic and biochemical properties . Journal of Neural Transmission. Supplementum . 67 . 67 . 139–148 . 2004 . 15068246 . 10.1007/978-3-7091-6721-2_12 . 978-3-211-40776-9 .
• Schultz SJ, Nigg EA . Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans . Cell Growth & Differentiation . 4 . 10 . 821–830 . October 1993 . 8274451 .
• Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N . Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21 . Biochemical and Biophysical Research Communications . 225 . 1 . 92–99 . August 1996 . 8769099 . 10.1006/bbrc.1996.1135 . 1996BBRC..225...92S .
• Guimerá J, Casas C, Pucharcòs C, Solans A, Domènech A, Planas AM, Ashley J, Lovett M, Estivill X, Pritchard MA . A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region . Human Molecular Genetics . 5 . 9 . 1305–1310 . September 1996 . 8872470 . 10.1093/hmg/5.9.1305 . free .
• Song WJ, Sternberg LR, Kasten-Sportès C, Keuren ML, Chung SH, Slack AC, Miller DE, Glover TW, Chiang PW, Lou L, Kurnit DM . Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region" . Genomics . 38 . 3 . 331–339 . December 1996 . 8975710 . 10.1006/geno.1996.0636 .
• Ohira M, Seki N, Nagase T, Suzuki E, Nomura N, Ohara O, Hattori M, Sakaki Y, Eki T, Murakami Y, Saito T, Ichikawa H, Ohki M . Gene identification in 1.6-Mb region of the Down syndrome region on chromosome 21 . Genome Research . 7 . 1 . 47–58 . January 1997 . 9037601 . 10.1101/gr.7.1.47 . free .
• Chen H, Antonarakis SE . Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2 . Human Genetics . 99 . 2 . 262–265 . February 1997 . 9048932 . 10.1007/s004390050350 . 26729330 .
• Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O'Dell TJ, Fung J, Weier HU, Cheng JF, Rubin EM . Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome . Nature Genetics . 16 . 1 . 28–36 . May 1997 . 9140392 . 10.1038/ng0597-28 . 29490013 .
• Dahmane N, Ghezala GA, Gosset P, Chamoun Z, Dufresne-Zacharia MC, Lopes C, Rabatel N, Gassanova-Maugenre S, Chettouh Z, Abramowski V, Fayet E, Yaspo ML, Korn B, Blouin JL, Lehrach H, Poutska A, Antonarakis SE, Sinet PM, Créau N, Delabar JM . Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome . Genomics . 48 . 1 . 12–23 . February 1998 . 9503011 . 10.1006/geno.1997.5146 .
• Xu X, Rich ES, Seldin DC . Murine protein kinase CK2 alpha': cDNA and genomic cloning and chromosomal mapping . Genomics . 48 . 1 . 79–86 . February 1998 . 9503019 . 10.1006/geno.1997.5154 . free .
• Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost HG . Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases . The Journal of Biological Chemistry . 273 . 40 . 25893–25902 . October 1998 . 9748265 . 10.1074/jbc.273.40.25893 . free .
• Wang J, Kudoh J, Shintani A, Minoshima S, Shimizu N . Identification of two novel 5' noncoding exons in human MNB/DYRK gene and alternatively spliced transcripts . Biochemical and Biophysical Research Communications . 250 . 3 . 704–710 . September 1998 . 9784410 . 10.1006/bbrc.1998.9392 . 1998BBRC..250..704W .
• Guimera J, Casas C, Estivill X, Pritchard M . Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome . Genomics . 57 . 3 . 407–418 . May 1999 . 10329007 . 10.1006/geno.1999.5775 .
• Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG, Cohen P . The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site . The Biochemical Journal . 355 . Pt 3 . 597–607 . May 2001 . 11311120 . 1221773 . 10.1042/bj3550597 .
• Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, Wu G, Wu D . Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1 . The Journal of Biological Chemistry . 277 . 38 . 35156–35161 . September 2002 . 12138125 . 10.1074/jbc.M206743200 . free . free . 10261/333520 .
• Martí E, Altafaj X, Dierssen M, de la Luna S, Fotaki V, Alvarez M, Pérez-Riba M, Ferrer I, Estivill X . Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system . Brain Research . 964 . 2 . 250–263 . February 2003 . 12576186 . 10.1016/S0006-8993(02)04069-6 . 35092325 .
• Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS . Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics . Journal of Medicinal Chemistry . 61 . 22 . 9791–9810 . November 2018 . 29985601 . 10.1021/acs.jmedchem.8b00185 . 51606533 .

Notes and References

1. Guimera J, Pritchard M, Nadal M, Estivill X . Minibrain (MNBH) is a single copy gene mapping to human chromosome 21q22.2 . Cytogenet Cell Genet . 77 . 3–4 . 182–4 . Sep 1997 . 9284911 . 10.1159/000134571 .
2. Bol SM, Moerland PD, Limou S, van Remmerden Y, Coulonges C, van Manen D, Herbeck JT, Fellay J, Sieberer M, Sietzema JG, van 't Slot R, Martinson J, Zagury JF, Schuitemaker H, van 't Wout AB . Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages . PLOS ONE . 6 . 2 . e17190 . 2011 . 21364930 . 3045405 . 10.1371/journal.pone.0017190 . 2011PLoSO...617190B . free .
3. Web site: Entrez Gene: DYRK1A dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A.
4. Noll C, Planque C, Ripoll C, Guedj F, Diez A, Ducros V, Belin N, Duchon A, Paul JL, Badel A, de Freminville B, Grattau Y, Bléhaut H, Herault Y, Janel N, Delabar JM . DYRK1A, a novel determinant of the methionine-homocysteine cycle in different mouse models overexpressing this Down-syndrome-associated kinase . PLOS ONE . 4 . 10 . e7540 . 2009 . 19844572 . 2760102 . 10.1371/journal.pone.0007540 . 2009PLoSO...4.7540N . free .
5. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J . Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders . Science . 338 . 6114 . 1619–22 . December 2012 . 23160955 . 10.1126/science.1227764 . 3528801. 2012Sci...338.1619O .
6. Courraud J, Quartier A, Drouot N, Zapata-Bodalo I, Gilet J, Benchoua A, Mandel JL, Piton A . DYRK1A roles in human neural progenitors . Frontiers in Neuroscience . 19 . 13 . 1533253 . March 2025 . 40182141 . 11966461 . 10.3389/fnins.2025.1533253 . free .
7. Skurat AV, Dietrich AD . Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases . J. Biol. Chem. . 279 . 4 . 2490–8 . January 2004 . 14593110 . 10.1074/jbc.M301769200 . free .
8. Web site: There She Goes creator explains family cameo in special episode . . 6 July 2023 . 21 June 2023.