Lysine demethylase 6B is a protein that in humans is encoded by the KDM6B (JMJD3) gene. [5]
Lysine demethylase 6B is a protein that in humans is encoded by the KDM6B (JMJD3) gene. [5]
KDM6B was found to be expressional increased during cardiac and endothelial differentiation of murine embryonic stem cells. [6]
A small molecule inhibitor (GSK-J1) has been developed to inhibit the jumonji domain of KDM6 histone demethylase family to modulate proinflammatory response in macrophages. [7]
Mutations of the KDM6B gene may cause neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, which was first described in 2019 by Stolerman et al. [8]
Standard laboratory exome sequencing can be used to identify the KDM6B gene variant.
A 2019 study [8] on symptoms from KDM6B variations reported:
A further 2023 international study [9] reported on the following clinical features among individuals with (likely) pathogenic KDM6B variants:
| Feature Name | p value | Total % |
|---|---|---|
| Males | 0.50 | 73% |
| Increased birth weight [>2 SD] | 0.33 | 17% |
| Increased weight [>2 SD] | 0.59 | 14% |
| Tall stature [>2 SD] | 1.0 | 8% |
| Macrocephaly [>2 SD] | 1.0 | 26% |
| At least one feature of overgrowth syndrome | 1.0 | 30% |
| Language/speech delay | 0.15 | 94% |
| Motor delay | 1.0 | 89% |
| Intellectual disability | 0.14 | 63% |
| Autism spectrum (ASD) | 0.51 | 61% |
| Behavior problems, non-ASD | 0.70 | 60% |
| Psychotic disorders [≥12 years old] | 1.0 | 20% |
| Seizures | 0.58 | 13% |
| Sleep disturbances | 0.09 | 32% |
| Movement disorder/gait disturbances/hypertonia/ataxia | 0.67 | 24% |
| Hypotonia | 1.0 | 57% |
| Neonatal feeding difficulties or gastroesophageal reflux | 1.0 | 51% |
| Constipation | 1.0 | 18% |
| Congenital heart disease | 0.58 | 13% |
| Cleft lip/palate/uvula | 0.03b | 4% |
| Genitourinary system abnormalities | 1.0 | 10% |
| Joint hypermobility | 1.0 | 42% |
| Scoliosis/kyphosis/lordosis | 0.58 | 13% |
| Syndactyly | 0.15 | 9% |
| Short fingers or toes | 1.0 | 9% |
| Broad fingers/fingertips/hands/toes/feet | 1.0 | 20% |
| Myopia/amblyopia | 0.08 | 33% |
| Strabismus | 0.58 | 13% |
| Hearing loss | 1.0 | 2% |
| Recurrent ear infections | 1.0 | 12% |
For patients reporting intellectual disability and/or developmental delay, approximately 0.12% have de novo alterations in the KDM6B gene.
Overlapping phenotypic features for patients between KDM6A associated with Kabuki syndrome and KDM6B variations include prominent ears, abnormal dentition, congenital heart disease, feeding difficulties, cryptorchidism, joint hyper-mobility, developmental delay, hypotonia, and behavioral difficulties.
According to a study published in 2022, pathologic mutations of KDM6B were found in five patients with cerebral folate deficiency. [10]
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.
Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genome by controlling the methylation of DNA and histones, and by extension, the chromatin state at specific gene loci.
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.
Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.
Lysine-specific demethylase 5B also known as histone demethylase JARID1B is a demethylase enzyme that in humans is encoded by the KDM5B gene. JARID1B belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.
Lysine-specific demethylase 4B is an enzyme that in humans is encoded by the KDM4B gene. KDM4B belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.
Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), is a protein which in humans is encoded by the KDM6A gene. It belongs to the 2-oxoglutarate (2OG)-dependent dioxygenase superfamily.
Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.
PHD finger protein 8 is a protein that in humans is encoded by the PHF8 gene.
ASH1L is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1.
WW domain-binding protein 4 is a protein that in humans is encoded by the WBP4 gene.
Lysine-specific demethylase 4D is an enzyme that in humans is encoded by the KDM4D gene. KDM4D belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.
Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.
Lysine demethylase 3A is a protein that in humans is encoded by the KDM3A gene.
Lysine methyltransferase 2E is a protein that in humans is encoded by the KMT2E gene.
TRPM3-related neurodevelopmental disorder is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system. The broad phenotype includes global developmental delay, intellectual disability, epilepsy, musculoskeletal anomalies, altered pain perception, ataxia, hypotonia, nystagmus, and cerebellar atrophy.
RNU4-2 Syndrome or ReNU syndrome is a neurodevelopmental disorder caused by de novo variants in the human gene RNU4-2, which encodes an RNA component of the major spliceosome. It is characterized by hypotonia, global developmental delay, severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, dysmorphic facial features, and brain anomalies, including ventriculomegaly.
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