Alternative titles; symbols
HGNC Approved Gene Symbol: JMJD1C
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38): 10:63,167,225-63,521,890 (from NCBI)
The JMJD1C gene encodes a putative histone demethylase and is involved in the epigenetic control of gene transcription (summary by Saez et al., 2016).
Thyroid hormone receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. They must specifically interact with various proteins as they progress from their initial translation and nuclear translocation to heterodimerization with retinoid X receptors (RXRs; see 180245), functional interactions with other transcription factors and the basic transcriptional apparatus, and eventually, degradation. To elucidate the mechanisms that underlie the transcriptional effects and other potential functions of TRs, Lee et al. (1995) used the yeast interaction trap to identify proteins that specifically interact with the ligand-binding domain of rat Tr-beta (THRB; 190160). They isolated HeLa cell cDNAs encoding several different TR-interacting proteins (TRIPs), including JMJD1C, which they called TRIP8.
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) isolated a partial cDNA for JMJD1C, which they designated KIAA1380. The deduced 1,265-amino acid protein, which is N-terminally truncated, shares significant similarity with rat testis-specific protein A (KDM3A; 611512). RT-PCR ESILA detected highest JMJD1C expression in ovary. Low JMJD1C expression was detected in most other adult and fetal tissues and specific adult brain regions examined, but expression was very low in fetal brain and absent in adult lung.
Using bioinformatics analysis, Katoh and Katoh (2003) determined the full-length coding sequence of TRIP8. The deduced 2,540-amino acid protein contains a bipartite nuclear localization signal in its N-terminal half and 2 TRIP8 homology domains (TRI8H1 and TRI8H2), a second bipartite nuclear localization signal, and a JMJC domain in its C-terminal half. The C-terminal part of TRI8H2 contains a C2HC4-type zinc finger-like motif. The domain organization of TRIP8 is similar to that of 5QNCA (KDM3B; 609373) and TSGA (KDM3A).
Using a fragment of androgen receptor (AR; 313700) as bait in a yeast 2-hybrid screen of a fetal brain cDNA library, followed by 3-prime and 5-prime RACE of adult human tissues, Wolf et al. (2007) cloned a splice variant of JMJD1C that they designated s-JMJD1C. The deduced 2,358-amino acid protein contains a zinc finger region, an AR-binding region, a nuclear localization signal, and a JMJC domain in its C-terminal half. Northern blot analysis detected variable expression of an approximately 9.5-kb s-JMJD1C transcript, with highest expression in heart, testis, and ovary. Within specific brain regions, highest expression was detected in cerebellum, with weaker expression in all other brain regions, but little to no expression in spinal cord. Immunohistochemical analysis of rat brain revealed abundant s-Jmjd1c expression in granular and pyramidal layers of cerebral cortex, hippocampus, basomedial nucleus of amygdala, and anterior hypothalamus. Fluorescence-tagged s-JMJD1C localized to nuclei of transfected PC3 human prostate cells.
Saez et al. (2016) found expression of the JMJD1C gene in various mouse and human brain regions. In HEK293 cells, endogenous JMJD1C was mainly found in the cytoplasm.
Lee et al. (1995) found that human TRIP8 interacted strongly with rat Thrb only in the presence of thyroid hormone. It also showed a ligand-dependent interaction with RXR-alpha (RXRA; 180245), but did not interact with glucocorticoid receptor (GCCR; 138040) under any condition.
Using protein pull-down assays, Wolf et al. (2007) confirmed that full-length s-JMJD1C and the isolated 112-amino acid AR-binding region of s-JMJD1C bound both liganded and unliganded AR. Both full-length s-JMJD1C and the AR-binding fragment enhanced androgen-induced transactivation of an AR reporter gene. Knockdown of s-JMJD1C in PC3 cells impaired induction of an AR target gene, TMPRSS2 (602060). S-JMJD1C more weakly enhanced ligand-induced transactivation of a glucocorticoid receptor reporter gene, but it had no effect on progesterone receptor (PGR; 607311) or mineralocorticoid receptor (NR3C2; 600983) reporter genes in PC3 cells. S-JMJD1C modestly enhanced triiodothyronine-induced activation of a TR reporter gene in SHSY5Y neuroblastoma cells. Gonadectomy reduced s-Jmjd1c expression in several adult rat brain regions, with greatest reduction in basomedial amygdala and pyramidal cortical layer.
Saez et al. (2016) found that siRNA-mediated knockdown of the JMJD1C gene in mouse primary neuronal hippocampal cells resulted in a significant reduction in the complexity and branching of dendritic processes.
Katoh and Katoh (2003) determined that the JMJD1C gene contains 26 exons and spans 300 kb.
By genomic sequence analysis, Katoh and Katoh (2003) mapped the JMJD1C gene to chromosome 10q21.3, where it lies less than 12 kb from the NRBF2 gene (616477) on the opposite strand.
Associations Pending Confirmation
Wang et al. (2014) reported novel and rare germline variants in JMJD1C among Japanese patients with intracranial germ cell tumors.
In 7 unrelated patients with a neurodevelopmental disability disorder, Saez et al. (2016) identified 7 different heterozygous nonsynonymous missense changes in the JMJD1C gene that were not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 500 controls. Sanger sequencing of the parents of 2 of the patients confirmed that the mutations occurred de novo: 1 woman with a clinical diagnosis of Rett syndrome (312750) carried a P163L variant (604503.0001) and a boy with intellectual disability carried a de novo T1187A variant. The patients were ascertained from a total of 215 patients who underwent mutational analysis of the JMJD1C gene, including 69 with autism spectrum disorders, 85 with intellectual disability, and 61 females with a clinical diagnosis of Rett syndrome. Parental samples were not available from the other 5 patients, so it could not be determined if an unaffected parent was a carrier or if the mutation occurred de novo in those patients.
This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder resembling Rett syndrome (312750) has not been confirmed.
In a 29-year-old woman with a clinical diagnosis of Rett syndrome, Saez et al. (2016) identified a de novo heterozygous c.488C-T transition (c.488C-T, NM_032776.1) in exon 4 of the JMJD1C gene, resulting in a pro163-to-leu (P163L) substitution at a highly conserved residue. The variant was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases, or in 500 controls. In vitro functional expression studies in HEK293 cells showed that the variant P163A protein had abnormal subcellular localization and was enriched in the chromatin fraction compared to wildtype. The variant protein also had a decreased activity to demethylate the DNA damage-response protein MDC1 (607593) and reduced binding to MECP2 (300005). In addition, siRNA-mediated knockdown of the JMJD1C gene in mouse primary neuronal hippocampal cells resulted in a significant reduction in the complexity and branching of dendritic processes.
Katoh, M., Katoh, M. Identification and characterization of TRIP8 gene in silico. Int. J. Molec. Med. 12: 817-821, 2003. [PubMed: 14533015]
Lee, J. W., Choi, H.-S., Gyuris, J., Brent, R., Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Molec. Endocr. 9: 243-254, 1995. [PubMed: 7776974] [Full Text: https://doi.org/10.1210/mend.9.2.7776974]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Saez, M. A., Fernandez-Rodriguez, J., Moutinho, C., Sanchez-Mut, J. V., Gomez, A., Vidal, E., Petazzi, P., Szczesna, K., Lopez-Serra, P., Lucariello, M., Lorden, P., Delgado-Morales, R., and 11 others. Mutations in JMJD1C are involved in Rett syndrome and intellectual disability. Genet. Med. 18: 378-385, 2016. [PubMed: 26181491] [Full Text: https://doi.org/10.1038/gim.2015.100]
Wang, L., Yamaguchi, S., Burstein, M. D., Terashima, K., Chang, K., Ng, H.-K., Nakamura, H., He, Z., Doddapaneni, H., Lewis, L., Wang, M., Suzuki, T., and 14 others. Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511: 241-245, 2014. [PubMed: 24896186] [Full Text: https://doi.org/10.1038/nature13296]
Wolf, S. S., Patchev, V. K., Obendorf, M. A novel variant of the putative demethylase gene, s-JMJD1C, is a coactivator of the AR. Arch. Biochem. Biophys. 460: 56-66, 2007. [PubMed: 17353003] [Full Text: https://doi.org/10.1016/j.abb.2007.01.017]