Alternative titles; symbols
HGNC Approved Gene Symbol: KDM5B
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:202,724,495-202,808,421 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | Intellectual developmental disorder, autosomal recessive 65 | 618109 | Autosomal recessive | 3 |
Methylation of histone H3 (see 602810) lys4 (H3K4) is an important epigenetic modification involved in gene activation. H3K4 di- and trimethylation (H3K4me2 and H3K4me3, respectively) residues mark the transcription start sites of actively transcribed genes, whereas a high level of H3K4 monomethylation (H3K4me1) is associated with enhancer sequences. Members of the KDM5 family of JmjC domain-containing proteins, including KDM5B, are demethylases of H3K4me2 and H3K4me3 and cause gene repression (summary by Shao et al., 2014).
Overexpression of ERBB2 (164870) correlates with a poor prognosis in breast cancer. Instead of functioning as a heterodimeric receptor, overexpressed ERBB2 appears to act as a constitutively signaling, autophosphorylating homodimer. To isolate genes whose expression is reversibly regulated by ERBB2 signaling as a homodimer, Lu et al. (1999) treated a mammary epithelial cell line overexpressing ERBB2 with an antibody (4D5) that downregulates its phosphorylation. Using isolated partial cDNAs to screen fetal brain and breast cancer cell line cDNA libraries, they isolated a full-length cDNA, which they designated PLU1. PLU1 encodes a deduced 1,544-amino acid protein containing 3 cysteine-rich zinc-binding PHD/LAP domains, a DNA-binding domain that is also found in the Drosophila dead ringer (dri) gene, 5 putative nuclear localization signals, and other conserved regions of unknown function. Northern blot analysis revealed expression of PLU1 transcripts at low levels in nonmalignant mammary cell lines and in colon cancer cell lines but at high levels in breast cancer cell lines. High expression in transformed breast cell lines decreased after treatment with 4D5. In situ hybridization analysis detected strong expression in the invasive but not in the benign components of primary breast carcinomas. Northern blot analysis detected high mRNA levels in normal testis and low levels in placenta, ovary, and tonsil. In situ hybridization analysis demonstrated expression in Sertoli cells. Western blot, immunohistochemical, and confocal microscopy analyses determined that PLU1 is expressed as a 170-kD protein in the nucleus. Permanent PLU1 transfectants could not be obtained, suggesting that overexpression of PLU1 may not be compatible with cell viability.
Kashuba et al. (2000) used a NotI-linking clone as a probe to isolate a novel putative member of the retinoblastoma-binding protein family, which they termed retinoblastoma-binding protein-2 homolog-1A (RBBP2H1A). They found that the maximum open reading frame encodes a deduced 1,681-amino acid protein containing 3 DNA-binding zinc finger domains and 2 bipartite nuclear localization signals. Except for an additional 137 amino acids, the protein is identical to PLU1. The RBBP2H1A protein shares 56% overall amino acid sequence identity with RBBP2 (180202), which plays an important role in RB (614041) tumor suppressor regulation. Northern blot analysis showed expression of approximately 6- and 7-kb transcripts in all tissues tested, with widely varying levels of expression among tissues. The highest level of expression was detected in testis and the lowest in skeletal muscle. No expression was detected in renal cell carcinoma biopsies or cell lines.
By bioinformatic analysis, Xiang et al. (2007) identified full-length JARID1B as a histone lysine demethylase. It has an N-terminal JmjN domain, followed by an ARID domain, a PHD domain, a JmjC domain, a zinc finger, and 2 C-terminal PHD domains.
Through bioinformatic and biochemical analysis, Xiang et al. (2007) identified JARID1B as an H3K4 demethylase. Overexpression of JARID1B in HeLa cells resulted in loss of tri-, di-, and monomethyl H3K4, but did not alter the methylation status of H3K9 or H3K36. In vitro biochemical experiments confirmed that JARID1B directly catalyzed the demethylation. Enzymatic activity required the JmjC domain of JARID1B and used Fe(II) and alpha-ketoglutarate as cofactors. Expression of JARID1B was upregulated in prostate cancer tissue compared with benign prostate hyperplasia. JARID1B associated with androgen receptor (AR; 313700) and regulated its transcriptional activity in reporter gene assays.
Shao et al. (2014) examined the changes of H3K4me and its key regulators in mouse oocytes and preimplantation embryos. They observed increased levels of H3K4me2 and H3K4me3 at the 1- to 2-cell stages, corresponding to the period of embryonic genome activation. The H3K4me2 level dramatically decreased at the 4-cell stage and remained low until the blastocyst stage. In contrast, the H3K4me3 level transiently decreased in 4-cell embryos but steadily increased to peak in blastocysts. Quantitative real-time PCR and immunofluorescence analyses showed that the high level of H3K4me2 during embryonic genome activation coincided with peak expression of its methyltransferase, Ash2l (604782), and a concomitant decrease in its demethylases, Kdm5b and Kdm1a (609132). H3K4me3 correlated with expression of its methyltransferase, Kmt2b (606834), and demethylase, Kdm5a (180202). Shao et al. (2014) proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos.
Borsos et al. (2019) generated high-resolution maps of genomic interactions with the nuclear lamina in mouse preimplantation embryos, which revealed that nuclear organization is not inherited from the maternal germline but is instead established de novo shortly after fertilization. The 2 parental genomes establish lamina-associated domains (LADs) with different features that converge after the 8-cell stage. Borsos et al. (2019) found that the mechanism of LAD establishment is unrelated to DNA replication. The authors showed that paternal LAD formation in zygotes is prevented by ectopic expression of Kdm5b, which suggested that LAD establishment may be dependent on remodeling of H3K4 methylation. Borsos et al. (2019) concluded that their data suggested a stepwise assembly model whereby early LAD formation precedes consolidation of topologically associating domains (TADs).
By fluorescence in situ hybridization, Lu et al. (1999) and Kashuba et al. (2000) mapped the RBBP2H1A gene to chromosome 1q32 in the same region as RBBP5 (600697).
In 3 unrelated patients with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109), Faundes et al. (2018) identified homozygous or compound heterozygous mutations in the KDM5B gene (605393.0001-605393.0005). The first patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The other 2 patients were identified from a cohort of 5,332 additional individuals from the DDD study who underwent exome sequencing. The KDM5B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variants were filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variants and studies of patient cells were not performed, but all mutations were nonsense or frameshift and were predicted to result in a loss of function.
Albert et al. (2013) found that homozygous deletion of Jarid1b (Kdm5b) in mice resulted in major neonatal lethality due to respiratory failure. Jarid1b-null embryos had neural defects, including disorganized cranial nerves, defects in eye development, and increased incidence of exencephaly and skeletal anomalies. Genomewide analysis of histone modification showed increased levels of H3K4me3 in Jarid1b knockout embryos during development, which resulted in abnormal expression of certain genes.
In an 18-year-old man (patient 12), born of consanguineous parents, with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109), Faundes et al. (2018) identified a homozygous c.4109T-G transversion (c.4109T-G, NM_001314042.1) in the KDM5B gene, resulting in a leu1370-to-ter (L1370X) substitution. The mutation, which was found by exome sequencing as part of the Deciphering Developmental Disorders (DDD) study, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 10-year-old boy (patient 13) with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109), Faundes et al. (2018) identified compound heterozygous mutations in the KDM5B gene: a c.2475-2A-G transition (c.2475-2A-G, NM_001314042.1), presumably resulting in a splice site mutation, and a c.895C-T transition, resulting in an arg299-to-ter (R299X; 605393.0003) substitution. The mutations were found by exome sequencing as part of the Deciphering Developmental Disorders (DDD) study. Segregation studies in the family were not performed. Functional studies of the variants and studies of patient cells were not performed, but both mutations were predicted to result in a loss of function.
For discussion of the c.895C-T transition (c.895C-T, NM_001314042.1) in the KDM5B gene, resulting in an arg299-to-ter (R299X) that was found in compound heterozygous state in a patient with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109) by Faundes et al. (2018), see 605393.0002.
In an 11-year-old boy with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109), Faundes et al. (2018) identified compound heterozygous mutations in the KDM5B gene: a 1-bp deletion (c.3906delC, NM_001314042.1), predicted to result in a frameshift and premature termination (Asn1302LysfsTer45), and a 1-bp duplication (c.622dupT; 605393.0005), also predicted to result in a frameshift and premature termination (Tyr208LeufsTer5). The mutations were found by exome sequencing as part of the Deciphering Developmental Disorders (DDD) study. Segregation studies in the family were not performed. Functional studies of the variants and studies of patient cells were not performed, but both mutations were predicted to result in a loss of function.
For discussion of the 1-bp duplication (c.622dupT, NM_001314242.1) in the KDM5B gene, predicted to result in a frameshift and premature termination (Tyr208LeufsTer5), that was found in compound heterozygous state in a patient with autosomal recessive intellectual developmental disorder-65 (MRT65; 618109) by Faundes et al. (2018), see 605393.0004.
Albert, M., Schmitz, S. U., Kooistra, S. M., Malatesta, M., Morales Torres, C., Rekling, J. C., Johansen, J. V., Abarategui, I., Helin, K. The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. PLoS Genet. 9: e1003461, 2013. [PubMed: 23637629] [Full Text: https://doi.org/10.1371/journal.pgen.1003461]
Borsos, M., Perricone, S. M., Schauer, T., Pontabry, J., de Luca, K. L., de Vries, S. S., Ruiz-Morales, E. R., Torres-Padilla, M.-E., Kind, J. Genome-lamina interactions are established de novo in the early mouse embryo. Nature 569: 729-733, 2019. [PubMed: 31118510] [Full Text: https://doi.org/10.1038/s41586-019-1233-0]
Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am. J. Hum. Genet. 102: 175-187, 2018. [PubMed: 29276005] [Full Text: https://doi.org/10.1016/j.ajhg.2017.11.013]
Kashuba, V., Protopopov, A., Podowski, R., Gizatullin, R., Li, J., Klein, G., Wahlestedt, C., Zabarovsky, E. Isolation and chromosomal localization of a new human retinoblastoma binding protein 2 homologue 1a (RBBP2H1A). Europ. J. Hum. Genet. 8: 407-413, 2000. [PubMed: 10878660] [Full Text: https://doi.org/10.1038/sj.ejhg.5200474]
Lu, P. J., Sundquist, K., Baeckstrom, D., Poulsom, R., Hanby, A., Meier-Ewert, S., Jones, T., Mitchell, M., Pitha-Rowe, P., Freemont, P., Taylor-Papadimitriou, J. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J. Biol. Chem. 274: 15633-15645, 1999. [PubMed: 10336460] [Full Text: https://doi.org/10.1074/jbc.274.22.15633]
Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development. In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014. [PubMed: 24619213] [Full Text: https://doi.org/10.1007/s11626-014-9741-6]
Xiang, Y., Zhu, Z., Han, G., Ye, X., Xu, B., Peng, Z., Ma, Y., Yu, Y., Lin, H., Chen, A. P., Chen, C. D. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc. Nat. Acad. Sci. 104: 19226-19231, 2007. [PubMed: 18048344] [Full Text: https://doi.org/10.1073/pnas.0700735104]