Alternative titles; symbols
HGNC Approved Gene Symbol: DUSP6
Cytogenetic location: 12q21.33 Genomic coordinates (GRCh38): 12:89,347,235-89,352,501 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.33 | Hypogonadotropic hypogonadism 19 with or without anosmia | 615269 | Autosomal dominant | 3 |
Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous subgroup of the type I cysteine-based protein-tyrosine phosphatase superfamily. DUSPs are characterized by their ability to dephosphorylate both tyrosine and serine/threonine residues. DUSP6 belongs to a class of DUSPs, designated MKPs, that dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (see 601795), JNK (see 601158), and p38 (see 600289) with specificity distinct from that of individual MKP proteins. MKPs contain a highly conserved C-terminal catalytic domain and an N-terminal Cdc25 (see 116947)-like (CH2) domain. MAPK activation cascades mediate various physiologic processes, including cellular proliferation, apoptosis, differentiation, and stress responses (summary by Patterson et al., 2009).
Muda et al. (1996) identified rat superior cervical ganglion cDNAs encoding 2 dual-specificity phosphatases that they designated MKP3 and MKPX (DUSP7; 602749).
Groom et al. (1996) identified cDNAs encoding the human MKP3 and MKPX homologs, which they called PYST1 and PYST2, respectively. Like other dual-specificity phosphatases, the N-terminal region of the predicted 381-amino acid PYST1 protein has 2 domains with significant homology to CDC25 (157680). Northern blot analysis revealed that PYST1 is expressed as a 3-kb mRNA in a variety of tissues, with the highest levels in heart and pancreas. By immunofluorescence of mammalian cells expressing epitope-tagged PYST1, Groom et al. (1996) showed that the protein is localized to the cytoplasm.
By RT-PCR, Furukawa et al. (1998) found that DUSP6 was expressed as 2 differently sized transcripts in all tissues tested.
Furukawa et al. (1998) determined that the DUSP6 gene contains 3 exons.
By analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH), Smith et al. (1997) mapped the DUSP6 gene to 12q22-q23. By FISH, Furukawa et al. (1998) localized the gene to 12q21.
By Northern blot analysis, Muda et al. (1996) found that nerve growth factor (see 162030) induced MKP3 expression in PC12 cells. By in situ hybridization, Muda et al. (1996) showed that metrazole-stimulated seizure activity induced MKP3 expression, rapidly and transiently, in specific regions of the brain. When expressed in mammalian cells, MKP3 blocked both the phosphorylation and enzymatic activation of the MAP kinase ERK2 (176948) by mitogens. Muda et al. (1996) concluded that MKP3 may play an important and specific role in regulating MAP kinase activities.
Groom et al. (1996) found that PYST1 dephosphorylated and inactivated MAP kinase in vitro and in vivo, but displayed very low activity towards the related stress-activated protein kinases (SAPKs; see 601158). When expressed in mammalian cells, PYST1 formed a physical complex with endogenous MAP kinase.
Furukawa et al. (1998) found decreased expression of DUSP6 in a subset of pancreatic cancer cell lines. Xu et al. (2005) determined that transcriptional suppression of DUSP6 in a subset of human pancreatic cancer cell lines was due to hypermethylation of CpG islands in intron 1. Among 12 cancer cell lines, methylation was detected in 5 of 8 cases with abolished expression of DUSP6, 4 of which were poorly differentiated adenocarcinoma. None of the 4 cases with preserved expression of DUSP6 showed methylation. The methylation state correlated with both the abolishment of protein expression and the histologic cancer subtype. Xu et al. (2005) suggested that DUSP6 acts as a tumor suppressor.
Using whole-genome analysis and RNA sequencing, Vo et al. (2019) identified Dusp6 as a genetic modifier of muscular dystrophy in the Sgcg (608896)-null D2 mouse strain. Dusp6 from the D2 mouse strain had a met62-to-ile (M62I) variant that was not present in other strains. The M62I change did not alter cytoplasmic localization of Dusp6 or overall expression of Dusp6 in C2C12 cells, but pull-down assays showed that M62I reduced the ability of Dusp6 to interact with Erk2, resulting in increased Erk1/Erk2 phosphorylation and activity. Inhibition of Dusp6 in myoblasts from different mouse strains resulted in dose-dependent increases in cell proliferation, whereas Dusp6 inhibition had little effect in D2 mice.
In 5 unrelated individuals with congenital hypogonadotropic hypogonadism (HH19; 615269), Miraoui et al. (2013) identified heterozygosity for missense mutations in the DUSP6 gene (602748.0001-602748.0004). In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene, either FGFR1 (136350.0028) and SPRY4 (607984.0001 and 607984.0003). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Maillet et al. (2008) found that Dusp6 -/- mice were viable and fertile; however, they had enlarged hearts, which was associated with higher rates of myocyte proliferation during embryonic and early postnatal development. Dusp6 -/- mice had increased basal Erk1 (601795)/Erk2 phosphorylation in the heart, spleen, kidney, brain, and fibroblasts, but loss of Dusp6 did not increase or prolong Erk1/Erk2 activation after stimulation. Dusp6 -/- embryonic fibroblasts also showed reduced rate of apoptosis compared with wildtype fibroblasts. Increased cardiac myocyte content in Dusp6 -/- mice was protective against cardiac injury following long-term pressure overload or experimental infarction in adult mice. Maillet et al. (2008) concluded that DUSP6 coordinates cellular development and survival and directly affects disease responsiveness in adulthood.
By studying wildtype and Mkp3 -/- mice after hindpaw surgery, Skopelja-Gardner et al. (2017) found that mechanical allodynia resolved over a 12-day period in wildtype mice, whereas it persisted in Mkp3 -/- mice. Mkp3 -/- mice exhibited higher numbers of infiltrating inflammatory cells than wildtype mice 1 day after surgery that returned to baseline by 12 days after surgery. In both wildtype and Mkp3 -/- mice, peripheral phosphorylated p38 levels were increased at 1 and 5 days after surgery and returned to basal levels the following week. Phosphorylated Erk1/2 followed a similar course in wildtype mice, but in Mkp3 -/- mice phosphorylated Erk1/2 levels remained elevated 12 days after surgery. Hypersensitivity and Erk1/2 phosphorylation were reduced by administration of a Mek (see 176872) inhibitor. Skopelja-Gardner et al. (2017) proposed that MKP3 is critical for normal resolution of acute postoperative allodynia in peripheral tissue, as they had observed previously in spine (Saha et al., 2013).
In 2 patients with congenital hypogonadotropic hypogonadism (HH19; 615269), Miraoui et al. (2013) identified heterozygosity for a c.566A-G transition in exon 2 of the DUSP6 gene, resulting in an asn189-to-ser (N189S) substitution at a conserved residue in the link between the rhodanese and dual-specificity phosphatase domains. The mutation was not found in 155 controls or in the 1000 Genomes Project database. The male and female patients were both anosmic; the female patient, who also carried a heterozygous missense mutation in the SPRY4 gene (S241Y; 607984.0002), had low bone mass.
In a male patient with congenital hypogonadotropic hypogonadism (HH19; 615269), Miraoui et al. (2013) identified heterozygosity for a c.545C-T transition in exon 2 of the DUSP6 gene, resulting in a ser182-to-phe (S182F) substitution at a highly conserved residue in the link between the rhodanese and dual-specificity phosphatase domains. The mutation was not found in 155 controls or in the 1000 Genomes Project database. The patient, who was anosmic and displayed abnormal dentition, also carried a heterozygous missense mutation in the FGFR1 gene (E692G; 136350.0028).
In a female patient with congenital hypogonadotropic hypogonadism (HH19; 615269), Miraoui et al. (2013) identified heterozygosity for a c.1037C-T transition in exon 3 of the DUSP6 gene, resulting in a thr346-to-met (T346M) substitution at a highly conserved residue in the dual-specificity phosphatase domain. The mutation was not found in 155 controls or in the 1000 Genomes Project database. The patient, who was anosmic and had hearing loss and low bone mass, also carried a heterozygous missense mutation in the SPRY4 gene (S241Y; 607984.0002).
In a female patient with congenital hypogonadotropic hypogonadism (HH19; 615269), Miraoui et al. (2013) identified heterozygosity for a c.229T-A transversion in exon 1 of the DUSP6 gene, resulting in a phe77-to-ile (F77I) substitution at a conserved residue in the rhodanese domain. The mutation was not found in 155 controls or in the 1000 Genomes Project database. The patient, who had a normal sense of smell, displayed abnormal dentition.
Furukawa, T., Yatsuoka, T., Youssef, E. M., Abe, T., Yokoyama, T., Fukushige, S., Soeda, E., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Horii, A. Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenet. Cell Genet. 82: 156-159, 1998. [PubMed: 9858808] [Full Text: https://doi.org/10.1159/000015091]
Groom, L. A., Sneddon, A. A., Alessi, D. R., Dowd, S., Keyse, S. M. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 15: 3621-3632, 1996. [PubMed: 8670865]
Maillet, M., Purcell, N. H., Sargent, M. A., York, A. J., Bueno, O. F., Molkentin, J. D. DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J. Biol. Chem. 283: 31246-31255, 2008. [PubMed: 18753132] [Full Text: https://doi.org/10.1074/jbc.M806085200]
Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
Muda, M., Boschert, U., Dickinson, R., Martinou, J.-C., Martinou, I., Camps, M., Schlegel, W., Arkinstall, S. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J. Biol. Chem. 271: 4319-4326, 1996. [PubMed: 8626780] [Full Text: https://doi.org/10.1074/jbc.271.8.4319]
Patterson, K. I., Brummer, T., O'Brien, P. M., Daly, R. J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J. 418: 475-489, 2009. [PubMed: 19228121] [Full Text: https://doi.org/10.1042/bj20082234]
Saha, M., Skopelja, S., Martinez, E., Alvarez, D. L., Liponis, B. S., Romero-Sandoval, E. A. Spinal mitogen-activated protein kinase phosphatase-3 (MKP-3) is necessary for the normal resolution of mechanical allodynia in a mouse model of acute postoperative pain. J. Neurosci. 33: 17182-17187, 2013. [PubMed: 24155322] [Full Text: https://doi.org/10.1523/JNEUROSCI.5605-12.2013]
Skopelja-Gardner, S., Saha, M., Alvarado-Vazquez, P. A., Liponis, B. S., Martinez, E., Romero-Sandoval, E. A. Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice. J. Pain Res. 10: 763-774, 2017. [PubMed: 28405172] [Full Text: https://doi.org/10.2147/JPR.S129826]
Smith, A., Price, C., Cullen, M., Muda, M., King, A., Ozanne, B., Arkinstall, S., Ashworth, A. Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7). Genomics 42: 524-527, 1997. [PubMed: 9205128] [Full Text: https://doi.org/10.1006/geno.1997.4756]
Vo, A. H., Swaggart, K. A., Woo, A., Gao, Q. Q., Demonbreun, A. R., Fallon, K. S., Quattrocelli, M., Hadhazy, M., Page, P. G. T., Chen, Z., Eskin, A., Squire, K., Nelson, S. F., McNally, E. M. Dusp6 is a genetic modifier of growth through enhanced ERK activity. Hum. Molec. Genet. 28: 279-289, 2019. [PubMed: 30289454] [Full Text: https://doi.org/10.1093/hmg/ddy349]
Xu, S., Furukawa, T., Kanai, N., Sunamura, M., Horii, A. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J. Hum. Genet. 50: 159-167, 2005. [PubMed: 15824892] [Full Text: https://doi.org/10.1007/s10038-005-0235-y]