Alternative titles; symbols
HGNC Approved Gene Symbol: KDM5A
Cytogenetic location: 12p13.33 Genomic coordinates (GRCh38) : 12:280,057-389,320 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.33 | El Hayek-Chahrour neurodevelopmental syndrome | 620820 | 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 KDM5A, are demethylases of H3K4me2 and H3K4me3 and cause gene repression (summary by Shao et al., 2014).
By searching for proteins that bind a region of the RB1 protein (614041) that interacts with viral oncoproteins, Defeo-Jones et al. (1991) isolated a partial cDNA encoding JARID1A, which they called RBP2.
Using the partial clone isolated by Defeo-Jones et al. (1991) to screen pre-B-cell leukemia cell line and fetal brain cDNA libraries, Fattaey et al. (1993) obtained a full-length cDNA encoding RBP2. The deduced 1,722-amino acid protein has a calculated molecular mass of 196 kD. RBP2 contains a potential N-terminal zinc finger motif, a central region with similarity to the engrailed family of homeotic genes (see EN1; 131290), and a C-terminal RB-binding motif. Northern blot analysis detected RBP2 expression at variable levels in all tissues examined, and Western blot analysis detected RBP2 expression in all human cell lines examined. Endogenous RBP2 migrated at an apparent molecular mass of 195 kD. Immunoprecipitation of fractionated glioblastoma cells indicated that RBP2 is a nuclear protein.
El Hayek et al. (2023) found that Kdm5a was ubiquitously expressed across all cell types in mouse hippocampus.
Defeo-Jones et al. (1991) determined that a sequence within RBP2 containing an LxCxE motif was required for its interaction with RB.
By immunoprecipitation of RBP2 from a myeloid leukemia cell line, Fattaey et al. (1993) confirmed interaction of RBP2 with RB in vivo. The interaction was disrupted in the presence of E7 viral oncoprotein.
To identify proteins that may modulate the activity of RBTN2 (LMO2; 180385), Mao et al. (1997) employed the yeast 2-hybrid assay to screen a human lymphocyte cDNA library using the RBTN2 LIM domain region as bait. They isolated a cDNA encoding the C-terminal region of RBBP2. The authors confirmed the interaction between RBTN2 and RBBP2 using in vitro binding assays and by coimmunoprecipitation of the 2 proteins. Deletion analysis showed that the second LIM domain of RBTN2 was necessary and sufficient for binding to the last 69 amino acids of RBBP2. The interaction between RBTN2 and RBBP2 had a functional consequence: the combination of RBBP2 and RBTN2 resulted in a higher level of transcription than RBTN2 alone in an in vitro assay. Mao et al. (1997) stated that the interaction of RBTN2 with RBBP2 suggests that RBTN2 may directly affect the activity of RBBP2 and/or RBTN2 may indirectly modulate the functions of the RB1 protein by binding to RBBP2.
Lopez-Bigas et al. (2008) found that RBP2 bound to the proximal promoter regions of genes belonging to 2 predominant classes: differentiation-independent genes, which were enriched for genes encoding mitochondrial proteins, and differentiation-dependent genes, which were enriched for genes encoding proteins involved in cell cycle control. About half of the RBP2 targets were positive for H3K4 trimethylation. Human SAOS-2 cells overexpressing RBP2 displayed abnormally short or fragmented mitochondria. Recruitment of RBP2 to the promoter of MFN2 (608507), which encodes a key mitochondrial component, correlated with decreased promoter activity and with significantly decreased H3K4 trimethylation of this promoter. Lopez-Bigas et al. (2008) concluded that RBP2 exerts inhibitory effects on multiple genes through direct interaction with their promoters.
Wang et al. (2009) reported that fusing an H3K4me3-binding PHD finger, such as the C-terminal PHD finger of PHF23 (612910) or JARID1A, to a common fusion partner nucleoporin-98 (NUP98; 601021), as identified in human leukemias (Reader et al., 2007; van Zutven et al., 2006), generated potent oncoproteins that arrested hematopoietic differentiation and induced acute myeloid leukemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors such as Hox(s) (see 142950), Gata3 (131320), Meis1 (601739), Eya1 (601653), and Pbx1 (176310), and enforced their active gene transcription in murine hematopoietic stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin boundary factors,' dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukemia stem cells. Wang et al. (2009) concluded that their studies represented the first report that deregulation of the PHD finger, an effector of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, leading to catastrophic cell fate decision making and oncogenesis during mammalian development.
DiTacchio et al. (2011) found that JARID1A forms a complex with CLOCK (601851)-BMAL1 (602550), which is recruited to the PER2 (603426) promoter. JARID1A increased histone acetylation by inhibiting histone deacetylase-1 (601241) function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1A in mammalian cells reduced PER promoter histone acetylation, dampened expression of canonic circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the JARID1A homolog 'lid' had lowered Per expression and similarly altered circadian rhythms. DiTacchio et al. (2011) concluded that JARID1A thus has a nonredundant role in circadian oscillator function.
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 (605393) and Kdm1a (609132). H3K4me3 correlated with expression of its methyltransferase, Kmt2b (606834), and demethylase, Kdm5a. Shao et al. (2014) proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos.
Batie et al. (2019) reported that hypoxia induces a rapid and hypoxia-inducible factor-independent induction of histone methylation in a range of human cultured cells. Genomic locations of histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3 after a brief exposure of cultured cells to hypoxia predicted the cell's transcriptional response several hours later. Batie et al. (2019) showed that inactivation of one of the JmjC-containing enzymes, lysine demethylase 5A (KDM5A), mimics hypoxia-induced cellular responses. Batie et al. (2019) concluded that their results demonstrated that oxygen sensing by chromatin occurs via JmjC-histone demethylase inhibition.
By analysis of KDM5A-knockout colon carcinoma cells and osteosarcoma cells treated with a KDM5A inhibitor, Kumbhar et al. (2021) demonstrated that KDM5A deficiency caused loss of cell viability due to PARP inhibition. Immunoprecipitation analysis indicated that KDM5A interacted with PARP1 (173870) and poly(ADP-ribose) (PAR) chains in cells in response to DNA damage. Analysis with purified proteins confirmed the direct interaction between KDM5A and PAR chains and identified a PAR interaction domain (PID) in the C terminus of KDM5A. The PID contained a coiled-coil domain and was unique to KDM5A, and it was sufficient for localization of KDM5A to the DNA damage sites in a PARP-dependent manner. The PID preferably bound to longer PAR chains, and KDM5A-PAR binding was essential for KDM5A recruitment and function at DNA damage sites to promote genome integrity and homologous recombination (HR) repair. In addition, KDM5A interacted with the histone variant macroH2A1.2 (see 610054), and macroH2A1.2 was required for KDM5A recruitment to DNA damage sites.
El Hayek et al. (2023) found that loss of Kdm5a altered hippocampal cell composition in mice. They found that 6 clusters of hippocampal cell types, 2 inhibitory clusters and 4 excitatory clusters (CA1.1, CA1.4, CA2, and CA3.4), were the most vulnerable to loss of Kdm5a. Kdm5a regulated common and unique genes in those 6 types of vulnerable hippocampal cells, and Kdm5a -/- mice showed accelerated hippocampal development compared to wildtype. Further analysis confirmed that Kdm5a regulated the development of excitatory clusters CA2 and CA3 as well as the 2 inhibitory cell populations, and that Kdm5a functioned early in development to specify proper CA1 cell identity.
Baens et al. (1995) characterized 117 cDNAs isolated by direct cDNA selection using pools of human chromosome 12p cosmids. Of these, 3 matched previously determined cDNA sequences, including the RBBP2 gene. STSs were developed for all cosmids. Regional assignment of the STSs by PCR analysis with somatic cell hybrids and fluorescence in situ hybridization showed that the loci mapped to chromosome 12p11.
Stumpf (2024) mapped the KDM5A gene to chromosome 12p13.33 based on an alignment of the KDM5A sequence (GenBank BC172533) with the genomic sequence (GRCh38).
In 5 patients from 3 families, including 2 sib pairs, with El Hayek-Chahrour neurodevelopmental syndrome (NEDEHC; 620820), El Hayek et al. (2020) identified homozygous mutations in the KDM5A gene (180202.0001-180202.0003). None of the mutations were present in the gnomAD database in 2020. Western blot analysis in lymphoblastoid cells from one of the sibs from family KD-2 demonstrated a truncated KDM5A protein. Western blot analysis in lymphoblastoid cells from patient KD-5-3 demonstrated reduced KDM5A protein expression. Expression of KDM5A with the c.2541+1G-T mutation (180202.0002) in HEK293 cells resulted in reduced KDM5A protein expression.
Associations Pending Confirmation
El Hayek et al. (2020) reported 3 patients with de novo heterozygous variants in the KDM5A gene with some similarities to patients with homozygous mutations. Patient KD-6-3 was a 40-year-old woman with a c.4048C-T transition, resulting in an arg1350-to-ter substitution. She was delivered cyanotic after a prolonged laber andvacuum extraction. She developed seizures on the first day of life.These complications make it difficult to interpret her phenotype. Patient KD-1-3 was a 5-year-old boy with a c.1A-T transversion, resulting in a met1-to-leu substitution. He had similar features to patients with homozygous mutations but no brain imaging information was available. Patient KD-3-3 was an 18-year-old man with a c.4283G-T transversion, resulting in an arg1428-to-leu substitution. He did not have absent speech but the authors noted that he had received extensive speech therapy since early childhood. He did not have motor impairment. No brain imaging information was available. An additional patient (patient KD-7-3) with similar features reported by El Hayek et al. (2020) had a 28.92-Mb region of loss of heterozygosity and a 50-kb microdeletion encompassing the KDM5A locus at 12p13.33 (chr12:458,096-507,789).
El Hayek et al. (2020) identified a C322X mutation in the mouse Kdm5a gene that was predicted to cause loss of function in an ENU mouse model with abnormal nesting behaviors and abnormal ultrasonic vocalizations. El Hayek et al. (2020) then used CRISPR editing to generate a mouse model with a homozygous 1-bp insertion in exon 13 of the Kdm5a gene resulting in a frameshift mutation and absence of protein expression. The mutant mice had abnormal repetitive behaviors, abnormal self-grooming, hyperactivity, abnormal socialization, and severe disabilities in learning and memory. Neurons from brains of the mutant mice showed a reduction in dendritic complexity, dendritic length, and dendritic spine density. Analysis of gene expression from the hippocampus of mutant mice demonstrated upregulation of genes involved in neurologic processes and decreased expression of genes involved with neurogenesis.
In 2 sibs (patients KD-2-3 and KD-2-4), born to consanguineous parents of Afghan ancestry, with El Hayek-Chahrour neurodevelopmental syndrome (NEDEHC; 620820), El Hayek et al. (2020) identified homozygosity for a 10-kb deletion (chr12.460,661-470,642, NM_001042603) including exons 6-9 of the KDM5A gene. The mutation, which was identified by whole-exome sequencing and confirmed by chromosomal microarray, was present in heterozygous state in the parents and unaffected sibs. The mutation was not present in the gnomAD database in 2020. Western blot analysis in lymphoblastoid cells from one of the affected sibs demonstrated a truncated protein.
In 2 sibs (patients KD-4-3 and KD-4-4), born to consanguineous Persian parents, with El Hayek-Chahrour neurodevelopmental syndrome (NEDEHC; 620820), El Hayek et al. (2020) identified homozygosity for a c.2541+1G-T transversion in the donor splice site of exon 18 of the KDM5A gene, predicted to result in a splicing abnormality. The mutation was identified by whole-exome sequencing and was not present in the gnomAD database in 2020. Expression of KDM5A with the c.2541+1G-T mutation in HEK293 cells resulted in severe reduction of KDM5A protein expression.
In a patient (patient KD-5-3), born to consanguineous parents, with El Hayek-Chahrour neurodevelopmental syndrome (NEDEHC; 610820), El Hayek et al. (2020) identified homozygosity for a c.1429T-G transversion in the KDM5A gene, resulting in a phe477-to-val (P477V) substitution. The mutation was identified by whole-exome sequencing and was not present in the gnomAD database in 2020. Western blot analysis in lymphoblastoid cells from the patient demonstrated reduced KDM5A protein expression.
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