Alternative titles; symbols
HGNC Approved Gene Symbol: KDM6A
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38) : X:44,873,188-45,112,779 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3 | Kabuki syndrome 2 | 300867 | X-linked dominant | 3 |
KDM6A, or UTX, mediates removal of repressive trimethylation of histone H3 (see 602810) lys27 (H3K27me3) to establish transcriptionally permissive chromatin (Faralli et al., 2016).
Greenfield et al. (1998) described the isolation of an X-linked homolog of Uty (see 400009), called Utx (ubiquitously transcribed TPR gene on the X chromosome), which is expressed from the inactive X chromosome in both mice and humans.
Greenfield et al. (1998) determined that the mouse Utx gene maps to the proximal region of the X chromosome in an interval containing the Maoa (309850) and Maob (309860) genes, thus placing it in band A2-A3. By Southern analysis of a panel of rodent/human somatic cell hybrids carrying derivative X chromosomes, Greenfield et al. (1998) mapped the human UTX gene to Xp11.3-p11.23. By fluorescence in situ hybridization on normal human metaphase spreads, they refined the localization to Xp11.2.
Crystal Structure
Kruidenier et al. (2012) presented a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 (611577) and UTX). The liganded structures of human and mouse JMJD3 provided novel insight into the specificity determinants for cofactor, substrate, and inhibitor recognition by the KDM6 subfamily of demethylases. Kruidenier et al. (2012) exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily, and demonstrated that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Kruidenier et al. (2012) concluded that their results resolved the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provided encouragement for designing small-molecule inhibitors to allow selective pharmacologic intervention across the JMJ family.
Mansour et al. (2012) demonstrated in mice and humans that the histone H3 methylated lys27 (H3K27) demethylase Utx regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors (OCT4, 164177; SOX2, 184429; KLF4, 602253) and uses its histone demethylase catalytic activity to facilitate induced pluripotent stem cell formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4, and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimeras generated from Utx-knockout pluripotent cells. Thus, Mansour et al. (2012) concluded that they identified Utx as a novel mediator with distinct functions during the reestablishment of pluripotency and germ cell development. They furthermore concluded that their findings highlighted the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.
Lan et al. (2007) showed that the JmjC-domain-containing related proteins UTX and JMJD3 (611577) catalyze demethylation of tri/dimethylated histone H3 (see 602810) lysine-27 (H3K27me3/2). UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in embryonic stem cells, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homolog resulted in misregulation of HOX genes and a striking posterior developmental defect, which was partially rescued by wildtype, but not by catalytically inactive, human UTX. Lan et al. (2007) concluded that, taken together, their findings identified a small family of H3K27 demethylases with important evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development.
Agger et al. (2007) showed that human JmjC domain-containing UTX and JMJD3 demethylate trimethylated lys27 on histone H3. Furthermore, the authors demonstrated that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, Agger et al. (2007) showed that UTX directly binds to the HOXB1 locus and is required for its activation. Finally, mutation of F18E9.5, a C. elegans JMJD3 ortholog, or inhibition of its expression, resulted in abnormal gonad development. Agger et al. (2007) concluded that, taken together, their results suggested that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (602113) (Issaeva et al., 2007), supported a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.
Lee et al. (2007) showed that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters (see 142950) and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A (see 602786). Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes (602113, 606833, respectively), and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Lee et al. (2007) concluded that their results suggested a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.
Chakraborty et al. (2019) reported that hypoxia promotes histone methylation in a HIF- and 2-hydroxyglutarate-independent manner. Chakraborty et al. (2019) found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B (611577), is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Chakraborty et al. (2019) concluded that oxygen directly affects chromatin regulators to control cell fate.
Kabuki Syndrome 2
By array CGH analysis in 2 Belgian girls with Kabuki syndrome (see KABUK2, 300867) who were negative for mutation in the MLL2 gene (602113), Lederer et al. (2012) identified de novo Xp11.3 microdeletions, both of which contained part or all of the KDM6A gene. In the 13-year-old girl, the 283.5-kb deletion included KDM6A exons 21 through 29, coding for the terminal part of the catalytic domain of KDM6A, and CXORF36 (300959). In the 10-year-old girl, the 815.7-kb deletion completely removed KDM6A, CXORF36, DUSP21 (300678) and FUNDC1 (300871). Sequencing of the KDM6A gene as well as targeted array CGH in a cohort of 22 MLL2-negative Kabuki syndrome patients revealed a de novo 45.4-kb intragenic deletion in a 2-year-old Italian boy (300128.0001). Although KDM6A escapes X inactivation, Lederer et al. (2012) found a skewed X-inactivation pattern in both girls (89:11 and 97:3, respectively), in which the deleted X chromosome was inactivated in the majority of the cells.
Miyake et al. (2013) analyzed the KDM6A gene in 32 patients with Kabuki syndrome who were negative for mutation in the MLL2 gene and identified nonsense mutations in 2 male patients and a 3-bp deletion in a female patient (300128.0002-300128.0004). The female patient had fewer dysmorphic features than the male patients, who displayed a more severe phenotype with multiple organ involvement. Miyake et al. (2013) suggested that the mutation type as well as X-inactivation pattern in affected organs in females may determine the severity of Kabuki syndrome.
Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 4 KDM6A mutations, 3 of which were novel.
In 2 brothers with Kabuki syndrome who were negative for mutation in the MLL2 gene, Lederer et al. (2014) identified a 4-bp deletion in the KDM6A gene (300128.0006). Their mother and maternal grandmother, who also carried the mutation, exhibited attenuated phenotypes. Lederer et al. (2014) reviewed the clinical features of all reported patients with KDM6A mutations and stated that the family studied by them represented the first instance of hereditary X-linked Kabuki syndrome.
Faundes et al. (2021) analyzed molecular data on 36 newly reported and 49 previously reported patients with heterozygous or hemizygous mutations in the KDM6A gene. Sixty-six KDM6A mutations were identified in 78 families, including 50 premature termination variants (PTV) in 62 patients from 59 families and 16 protein-altering variants (PAVs) in 23 patients from 19 families. The PTVs were all classified as pathogenic. Fifteen PTVs were nonsense mutations, 14 affected canonical splice sites, 12 were frameshift mutations, 8 were gross deletions, and 1 resulted from a chromosome translocation disrupting the KDM6A gene. In 42 patients, including 13 males and 29 females, the KDM6A PTVs were de novo, and in 6 patients the mutations were inherited from the mother. Of the 16 PAVs, 12 were classed as pathogenic or likely pathogenic, 3 as variants of uncertain significance, and 1 as likely benign. Thirteen of the PAVs were missense, 2 were in-frame deletions, and 1 was an indel. Eight PAVs, in 2 males and 6 females, were de novo. Ten patients inherited the PAV from their mother, and 1 patient inherited the mutation from her father. Inheritance of the PAVs was not known in 4 patients.
Somatic Mutations
Van Haaften et al. (2009) described inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes.
Gozdecka et al. (2018) demonstrated that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (400009). In keeping with this, Gozdecka et al. (2018) demonstrated concomitant loss/mutation of KDM6A and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27 trimethylation but significant and bidirectional alterations in H3K27 acetylation and chromatin accessibility; a predominant loss of H3K4 monomethylation modifications; alterations in ETS (see ETS1, 164720) and GATA-factor (see GATA2, 137295) binding; and altered gene expression after UTX loss. By integrating proteomic and genomic analyses, Gozdecka et al. (2018) linked these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex, and enhanced pioneering activity of ETS factors during evolution to acute myeloid leukemia (AML; 601626). Gozdecka et al. (2018) concluded that their findings identified a dual role for UTX in suppressing AML via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.
Miyake et al. (2013) used mutation detection methods to screen 81 patients with Kabuki syndrome and identified KDM6A mutations in 5 (6.2%). Of the 5 mutations, including 2 that were novel, 4 were protein-truncating and 1 was an in-frame deletion in the Jumonji C domain. High-arched eyebrows, short fifth fingers, and infantile hypotonia were less commonly seen in patients with KDM6A mutations than in those with MLL2 mutations. All of the patients with KDM6A mutations had short stature and postnatal growth retardation, compared with only half of patients with MLL2 mutations. Among the 2 female patients with KDM6A mutations, one (KMS-65) with an in-frame deletion (300128.0004) had a random X-inactivation pattern, whereas the other (KMS-81) with a frameshift truncating mutation (300128.0005) showed marked skewing.
Faundes et al. (2021) analyzed molecular and clinical data in 80 patients with heterozygous or hemizygous mutations in the KDM6A gene. Patients with protein-altering variants (PAVs) had shorter birth lengths compared to patients with protein termination variants (PTVs). Patients with PTVs had more impaired intellectual development (97.6% vs 80%) and a higher frequency of central nervous system anomalies (71.4% vs 28.6%) compared to patients with PAVs, although the difference did not reach statistical significance. Faundes et al. (2021) concluded that individuals with PTVs overall have a more severe phenotype, and the phenotypes of patients with PAVs are more variable.
Van Laarhoven et al. (2015) used morpholino antisense oligonucleotides to knock down the 2 orthologs of KDM6A in zebrafish, Kdm6a and Kdm6al, and at 5 days postfertilization they observed hypoplasia of the branchial arches, the Meckel and ceratohyal cartilage, and the cleithrum and opercle in Kdm6a morphants; Kdm6al morphants did not exhibit craniofacial defects. Coinjection with in vitro synthesized KDM6A resulted in partial rescue of the craniofacial phenotype. In addition, at 48 hours postfertilization Kdm6a and Kdm6al morphants exhibited abnormal development of the atria and/or ventricle as well as prominent bulging of the myocardial wall, and Kdm6al morphants also showed progression through cardiac looping morphogenesis that was significantly lower than that observed with wildtype. When compared with wildtype embryos, cross-sectional areas of the brains of morphants were notably reduced and had a reduced cell layer thickness within the hypothalamus, optic tectum, and midbrain tegmentum. Analysis of neural precursor cell (NPC) markers demonstrated that morphant NPCs are defective in their ability to differentiate in the forebrain and midbrain; the differentiation defects were not observed in the hindbrain.
Faralli et al. (2016) noted that loss of Utx is embryonic lethal in female mice, whereas male mice lacking Utx survive due to expression of Uty, a Utx paralog that lacks H3K27 demethylase activity. They generated male and female mice with a conditional deletion (mko) of Utx in adult skeletal muscle stem cells, or satellite cells (SCs), which reside along muscle fibers. After cardiotoxin treatment, wildtype mice regenerated healthy myofibers, but female Utx mko/mko mice exhibited decreased myofiber density with increased necrosis and inflammatory cell infiltration. Male Utx mko/Y mice also showed impaired myofiber regeneration, suggesting that the H3K27 demethylase activity of Utx is required for SC-mediated adult muscle regeneration. Female mko heterozygotes showed normal muscle regeneration, whereas wildtype mice treated with an H3K27 inhibitor did not. Immunofluorescence analysis of myofiber explants demonstrated Utx expression in SCs at all stages of muscle regeneration, along with Pax7 (167410)-, Myod (159970)-, and Myog (159980)-expressing cell populations. However, loss of Utx or its demethylase activity impaired proliferation, Myog expression, and initiation of differentiation by progenitor cells. Functional analyses showed that Utx mediated terminal differentiation of muscle progenitor cells through removal of repressive H3K27me3 marks at key genes involved in the formation of functional myotubes, including Myog. Faralli et al. (2016) concluded that UTX H3K27 demethylase activity is essential in muscle regeneration after muscle injury. In a commentary on the work of Faralli et al. (2016), Liu and Rando (2016) noted the important insights the study provided into the contribution of epigenetic regulation in stem cell-mediated regeneration of adult tissues.
In a 2-year-old Italian boy with a typical Kabuki syndrome phenotype (KABUK2; 300867), Lederer et al. (2012) identified hemizygosity for a de novo 45.4-kb intragenic deletion from genomic coordinate chrX:44,866,302 to 44,912,718 (GRCh37/hg19), removing exons 5 through 9 of the KDM6A gene.
In a 14-year-old Japanese boy with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a 3717G-A transition in the KDM6A gene, resulting in a trp1239-to-ter (W1239X) substitution. Parental DNA was unavailable.
In a 22-year-old Japanese man with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a 1555C-T transition in the KDM6A gene, resulting in an arg519-to-ter (R519X) substitution. Parental DNA was unavailable.
In a 21-year-old woman with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a de novo heterozygous 3-bp deletion (c.3354_3356delTCT) in the KDM6A gene, resulting in the in-frame deletion of a highly conserved residue (leu1119del) in the catalytic Jumonji-C (JmjC) domain. The mutation was not present in either of her parents. The patient showed a random pattern of X inactivation, with a 57:43 ratio in genomic DNA from peripheral leukocytes.
In a female patient (KMS-81) with Kabuki syndrome-2 (KABUK2; 300867) who showed large front teeth with wide interdentium, Miyake et al. (2013) identified a 4-bp deletion in the KDM6A gene (c.1909_1912delTCTA) predicted to result in a frameshift and premature termination (Ser637ThrfsTer53). The patient showed a skewed X-inactivation pattern.
In 2 brothers with Kabuki syndrome-2 (KABUK2; 300867), Lederer et al. (2014) identified a 4-bp deletion (c.2515_2518del) in exon 17 of the KDM6A gene, causing a frameshift predicted to result in a premature termination codon (Asn839ValfsTer27). Their mother and maternal grandmother, who exhibited attenuated phenotypes, also carried the mutation, which was not found in an unaffected maternal aunt or in 144 controls.
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