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KMT2B
lysine methyltransferase 2B
KMT2B encodes a histone methyltransferase enzyme that regulates gene expression, with pathogenic variants linked to childhood-onset dystonia and related neurodevelopmental disorders. The KMT2B gene provides instructions for producing a protein that modifies histones, the structural components around which DNA wraps.
KMT2B is located on the long (q) arm of chromosome 19, at band 19q13.12. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 19 in the library →Overview
KMT2B (lysine methyltransferase 2B) is located on chromosome 19 and produces a protein essential for chromatin modification. The protein acts as a histone methyltransferase, catalysing the addition of methyl groups to lysine residues on histone H3, thereby influencing chromatin structure and gene transcription. This regulatory activity is particularly important during nervous system development.
Pathogenic variants in KMT2B follow an autosomal dominant inheritance pattern, meaning a single altered copy can cause disease. These variants are recognised causes of childhood-onset dystonia (DYT28) and related movement disorders, often accompanied by developmental delay and intellectual disability. The gene appears on multiple NHS clinical panels for neurological and developmental conditions, reflecting its clinical significance in the UK diagnostic pathway.
What the gene does
The KMT2B protein functions as a histone methyltransferase within multi-protein complexes that regulate gene expression. Specifically, it catalyses the trimethylation of histone H3 at lysine 4 (H3K4me3), a modification associated with active gene transcription. By depositing this methyl mark at gene promoters, KMT2B helps maintain appropriate expression patterns during development and throughout life.
This methyltransferase activity is crucial for neuronal differentiation and the maintenance of brain cell identity. The protein works in conjunction with other chromatin regulators to ensure genes required for normal brain function remain accessible to transcriptional machinery. KMT2B also contains DNA-binding motifs that help target the enzyme to specific genomic regions. The balance of histone methylation controlled by KMT2B appears particularly critical in the basal ganglia, brain structures that coordinate movement and are affected in dystonia.
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Chromosome location
KMT2B is located on the long arm of chromosome 19 at position 19q13.12. The gene spans a substantial genomic region and encodes a large protein of 2,715 amino acids. The chromosomal location places KMT2B within a gene-rich region of the genome, though the specific exon count and detailed transcript architecture are subject to ongoing refinement as genome annotation improves.
Protein structure
The KMT2B protein comprises 2,715 amino acids organised into distinct functional regions. The N-terminal region contains a menin-binding motif (around amino acids 17-36) that mediates interaction with the menin protein, anchoring KMT2B within larger chromatin-modifying complexes. The N-terminal portion also includes three A.T hook DNA-binding motifs (at amino acids 37-44, 110-117, and 357-365) that facilitate attachment to AT-rich DNA sequences.
The protein contains a CXXC-type zinc finger (amino acids 959-1,006) that recognises unmethylated CpG dinucleotides in DNA, helping to target the enzyme to gene promoters. Two PHD-type zinc fingers (amino acids 1,201-1,252 and 1,249-1,303) are present in the C-terminal region, contributing to chromatin binding and protein-protein interactions. Extensive disordered regions are interspersed throughout the sequence, providing flexibility that may facilitate assembly of the multi-protein complexes required for histone methylation activity.
Key variants
Pathogenic variants in KMT2B predominantly consist of loss-of-function alterations, including nonsense variants, frameshift insertions or deletions, and splice-site changes that disrupt normal protein production. Missense variants affecting critical functional domains have also been identified. The distribution of pathogenic variants across the gene suggests that having only one working copy of the gene (haploinsufficiency) cannot provide sufficient enzyme activity, which underlies the disease mechanism in most cases.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1127_1130del | p.Lys376fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.12_24dup | p.Ser9fs | Pathogenic | ★★☆☆ | not provided |
c.15_24dup | p.Ser9fs | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual developmental disorder, autosomal dominant 68 |
c.1633C>T | p.Arg545Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dystonia 28, childhood-onset |
c.1656dup | p.Lys553fs | Pathogenic | ★★☆☆ | Dystonia 28, childhood-onset |
c.1690C>T | p.Arg564Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dystonia 28, childhood-onset |
c.17_23dup | p.Ser9fs | Pathogenic | ★★☆☆ | Intellectual developmental disorder, autosomal dominant 68 |
c.3145dup | p.Ala1049fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.3400C>T | p.Gln1134Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.4053_4063del | p.Glu1351fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic KMT2B variants cause DYT28 childhood-onset dystonia, a movement disorder characterised by sustained or intermittent muscle contractions leading to abnormal postures and repetitive movements. Affected individuals typically develop symptoms in early childhood, often presenting initially with lower limb dystonia that may progress to involve other body regions. Many individuals also experience developmental delay and intellectual disability (learning disability in UK clinical terminology-these terms refer to the same condition). Severity and additional neurological features vary. The condition demonstrates variable expressivity, with symptom severity and progression differing among affected individuals even within the same family.
Inheritance pattern
Conditions caused by pathogenic KMT2B variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
KMT2B holds strong evidence classification on multiple NHS Genomic Medicine Service panels. It appears on the Childhood onset dystonia, chorea or related movement disorder panel (R57) and the Adult onset dystonia, chorea or related movement disorder panel (R56), reflecting its role across age groups. The gene is also included in the Intellectual disability panel (R29), Early onset dystonia panel, and Structural basal ganglia disorders panel. Additional memberships include the Fetal anomalies panel (R21), Severe microcephaly panel (R88), and the Developmental Disorders Genotype-to-Phenotype (DDG2P) database, underscoring its relevance to neurodevelopmental assessment in UK clinical practice.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the KMT2B gene do?
KMT2B provides instructions for making a histone methyltransferase enzyme that adds methyl chemical tags to histone proteins. This modification influences which genes are active in cells, particularly during brain development.
How is KMT2B-related dystonia inherited?
KMT2B-related conditions follow an autosomal dominant pattern, meaning an altered gene copy inherited from one parent can cause the condition. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant.
Can KMT2B variants be detected before symptoms appear?
Genetic testing can identify KMT2B variants in individuals without symptoms, including through prenatal or carrier screening. However, the presence of a variant does not predict exact symptom severity or age of onset, and clinical geneticists can discuss the implications of test results in the context of family history.