Alternative titles; symbols
HGNC Approved Gene Symbol: DYRK1B
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:39,825,350-39,834,162 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Abdominal obesity-metabolic syndrome 3 | 615812 | Autosomal dominant | 3 |
DYRK1B is a bipartite kinase that is activated by autophosphorylation of tyrosine during translation and phosphorylates its substrates at specific serine/threonine residues (Bhat et al., 2022).
The DYRK1A gene (600855), located on human chromosome 21 and encoding a dual-specificity protein kinase, is the human homolog of the Drosophila 'minibrain' gene. The minibrain protein product, mnb, is involved in postembryonic neurogenesis. By performing RACE on human testis RNA using primers designed to the catalytic domain of DYRK1A, Leder et al. (1999) isolated a partial DYRK1B cDNA; they obtained the complete coding sequence of human DYRK1B by PCR cloning from human testis cDNA. The putative DYRK1B peptide has a domain structure similar to that of DYRK1A, with a kinase domain flanked by a 110-amino acid N-terminal domain and a 198-amino acid C-terminal domain. Human DYRK1A and DYRK1B proteins are 84% identical in the N-terminal and catalytic domains but show no extended similarity in the C-terminal region. Northern blot analysis detected a 2.4-kb DYRK1B transcript in testis and skeletal muscle. Expression of DYRK1B as a GFP fusion protein in COS-7 cells localized the protein to the nucleus. Human and mouse DYRK1B proteins share 97% sequence identity.
Lee et al. (2000) cloned the same gene, which they designated MIRK for 'minibrain-related kinase.' They found that the encoded protein kinase enables colon carcinoma cells to survive under certain stress conditions. MIRK is a mitogen-activated protein kinase substrate but is downregulated by activated extracellular signal-regulated kinases (ERKs) in vivo. MIRK contains a PEST region characteristic of rapidly turned over proteins and is broken down to a 57-kD form only in the nucleus. MIRK mRNA levels were elevated in several types of carcinomas, and MIRK protein was detected in each of 7 colon carcinoma cell lines. Mirk was expressed at a higher protein level in Western blots from 3 of 8 colon cancers compared with paired normal colon tissue, suggesting that Mirk plays a role in the evolution of a subset of colon cancers. MIRK is not mutated in colon carcinomas.
Lee et al. (2000) determined that the DYRK1B gene has 11 exons and spans 8.8 kb of genomic DNA.
Leder et al. (1999) used a human/hamster radiation hybrid panel to map the DYRK1B gene to chromosome 19q12-q13.11. By sequence analysis, Lee et al. (2000) mapped the gene to 19q13.1.
Lim et al. (2002) found that MIRK coimmunoprecipitated with PCBD2 (609836) and bound to PCBD2 in GST pull-down assays. MIRK enhanced transcriptional activity of HNF1-alpha (TCF1; 142410) in a dose-dependent manner. MIRK, PCBD2, and HNF1-alpha formed a complex. MIRK also coimmunoprecipitated with the MAPK kinase MKK3 (MAP2K3; 602315), an upstream activator of p38. MKK3 enhanced MIRK kinase activity as well as the transcriptional activation of HNF1-alpha by MIRK.
Keramati et al. (2014) performed functional characterization of the DYRK1B gene and observed that the nonmutant protein inhibited the SHH (600725) and WNT (see 164820) pathways, thereby enhancing adipogenesis. In addition, DYRK1B promoted expression of the gluconeogenic enzyme glucose-6-phosphatase (see 613742).
Lee et al. (2016) reported that DYRK1A (600855) and DYRK1B kinases phosphorylate ID2 (600386) on threonine-27 (thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (EGLN2; 606424). ID2 binds to the VHL (608537) ubiquitin ligase complex, displaces VHL-associated cullin-2 (603135), and impairs HIF2-alpha (603349) ubiquitylation and degradation. Phosphorylation of thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2-alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2-alpha activity. Conversely, elevated expression of DYRK1 phosphorylates thr27 of ID2, leading to HIF2-alpha destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma.
In affected members of 3 multigenerational Iranian families with autosomal dominant metabolic syndrome and early-onset coronary artery disease (AOMS3; 615812), Keramati et al. (2014) identified heterozygosity for a missense mutation in the DYRK1B gene (R102C; 604556.0001) that segregated with disease in all 3 families and was not found in controls. Functional characterization showed gain of function with the R102C allele. Analysis of the DYRK1B gene in 300 morbidly obese Caucasian individuals with coronary artery disease and multiple metabolic phenotypes identified heterozygosity for another missense mutation (H90P; 604556.0002) in 5 unrelated patients.
Using electronic medical records of 7,800 participants in the Geisinger MyCode Project, Mirshahi et al. (2014) performed a 'phenomewide' association study involving an L28P variant of DYRK1B predicted to be damaging, and found a significant protective effect of L28P in 42 heterozygotes against type 2 diabetes (p = 0.002) as well as a trend toward a protective effect against hypertension. They concluded that some DYRK1B variants are associated with autosomal dominant protective effects.
Bhat et al. (2022) found that Dyrk1b expression was upregulated in livers of mice fed a high-calorie diet and in human patients with nonalcoholic steatohepatitis (NASH). Overexpression of Dyrk1b in liver caused steatosis and hyperlipidemia in mice, independent of Dyrk1b kinase activity. In contrast, liver-specific knockdown, but not global knockout, of Dyrk1b conferred significant protection against diet-induced hepatic steatosis and hypertriglyceridemia in mice. Dyrk1b stimulated hepatic de novo lipogenesis (DNL), hepatic triacylglycerol (TAG) secretion, and fatty acid (FA) uptake, and steatosis induced by Dyrk1b overexpression was caused by increased DNL and FA uptake, but not reduced FA oxidation. Rictor (609022), an obligate mTorc2 (see 601231) subunit, was the upstream regulator of the proteome altered by Dyrk1b, and Dyrk1b stimulated phosphorylation and activation of mTORC2 in a kinase-independent manner in liver. Moreover, hepatocyte-specific disruption of mTorc2 rescued hyperlipidemia, steatosis, and inflammation in mice overexpressing Dyrk1b in liver, supporting the effects of Dyrk1b in induction of DNL, hepatic steatosis, fibrosis, and inflammation. Further analysis indicated that Dyrk1b also caused insulin resistance by increasing plasma membrane sn-1,2-diacylglycerol, leading to translocation of Pkc-epsilon (PRKCE; 176975) and reduced insulin receptor (INSR; 147670) kinase activity.
In 3 multigenerational Iranian families segregating autosomal dominant abdominal obesity-metabolic syndrome (AOMS3; 615812) and early-onset coronary artery disease, Keramati et al. (2014) identified a heterozygous c.304C-T transition in the DYRK1B gene, resulting in an arg102-to-cys (R102C) substitution at a highly conserved residue in the kinase-like domain. The mutation, which segregated completely with disease in all 3 families, was not found in 2,000 ethnically matched Iranian controls or 3,600 Caucasian controls from the United States, or in samples from 2,500 individuals in the Allele Frequency Database, 5,000 exomes from the Yale Center for Genome Analysis database, or 5,400 exomes in the NHLBI ESP5400 database. Functional analysis of transfected 3T3-L1 cells showed that accumulation of intracellular lipid was significantly greater with R102C than wildtype DYRK1B, and cells expressing the R102C variant were able to transform into mature adipocytes without requiring adipogenic medium. Expression levels of CEBPA (116897), PPARG (601487) isoforms 1 and 2, and PGC1A (PPARGC1A; 604517) were higher, and those of GLI1 (165220) and p27(KIP1) (CDKN1B; 600778) were lower in cells transfected with the R102C mutant compared to wildtype. In addition, WNT (see 164820) signaling activity was lower in mutant cells compared to wildtype.
In 5 unrelated morbidly obese Caucasian individuals with coronary artery disease and multiple metabolic phenotypes (AOMS3; 615812), Keramati et al. (2014) identified a heterozygous c.179A-C transversion in the DYRK1B gene, resulting in a his90-to-pro (H90P) substitution at a highly conserved residue in the nuclear localization domain. Functional analysis of transfected HepG2 cells showed that expression of glucose-6-phosphatase (see 613742) was significantly higher with H90P than wildtype. DNA samples from family members of 1 of the probands showed a consistent pattern of cosegregation of the mutation with features of metabolic syndrome in an autosomal dominant fashion. Five members of the family had died from myocardial infarction between 50 and 60 years of age.
Bhat, N., Narayanan, A., Fathzadeh, M., Kahn, M., Zhang, D., Goedeke, L., Neogi, A., Cardone, R. L., Kibbey, R. G., Fernandez-Hernando, C., Ginsberg, H. N., Jain, D., Shulman, G. I., Mani, A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. J. Clin. Invest. 132: e153724, 2022. [PubMed: 34855620] [Full Text: https://doi.org/10.1172/JCI153724]
Keramati, A. R., Fathzadeh, M., Go, G.-W., Singh, R., Choi, M., Faramarzi, S., Mane, S., Kasaei, M., Sarajzadeh-Fard, K., Hwa, J., Kidd, K. K., Babaee Bigi, M. A., Malekzadeh, R., Hosseinian, A., Babaei, M., Lifton, R. P., Mani, A. A form of the metabolic syndrome associated with mutations in DYRK1B. New Eng. J. Med. 370: 1909-1919, 2014. [PubMed: 24827035] [Full Text: https://doi.org/10.1056/NEJMoa1301824]
Leder, S., Weber, Y., Altafaj, X., Estivill, X., Joost, H.-G., Becker, W. Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. Biochem. Biophys. Res. Commun. 254: 474-479, 1999. [PubMed: 9918863] [Full Text: https://doi.org/10.1006/bbrc.1998.9967]
Lee, K., Deng, X., Friedman, E. Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells. Cancer Res. 60: 3631-3637, 2000. [PubMed: 10910078]
Lee, S. B., Frattini, V., Bansal, M., Castano, A. M., Sherman, D., Hutchinson, K., Bruce, J. N., Califano, A., Liu, G., Cardozo, T., Iavarone, A., Lasorella, A. An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529: 172-177, 2016. [PubMed: 26735018] [Full Text: https://doi.org/10.1038/nature16475]
Lim, S., Jin, K., Friedman, E. Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1-alpha. J. Biol. Chem. 277: 25040-25046, 2002. Note: Erratum: J. Biol. Chem. 279: 5047 only, 2004. [PubMed: 11980910] [Full Text: https://doi.org/10.1074/jbc.M203257200]
Mirshahi, T., Murray, M. F., Carey, D. J. The metabolic syndrome and DYRK1B. (Letter) New Eng. J. Med. 371: 784-785, 2014. [PubMed: 25140973] [Full Text: https://doi.org/10.1056/NEJMc1408235]