KMT2D Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the KMT2D gene, its protein product, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | KMT2D |
|---|---|
| Full Name | lysine methyltransferase 2D |
| Gene Type | protein coding |
| Chromosomal Location | 12q13.12 |
| NCBI Gene ID | 8085 ncbi.nlm.nih.gov/gene/8085 |
| Ensembl ID | ENSG00000167548 |
| UniProt ID | O14686 |
| OMIM ID | 602113 |
| HGNC ID | 7133 |
| Aliases | MLL2, ALR, CAGL114, KABUK1, TNRC21 |
Description
KMT2D (lysine methyltransferase 2D), also known as MLL2, encodes a large histone-lysine N-methyltransferase that specifically methylates histone H3 at lysine 4 (H3K4). This methylation mark is associated with active gene transcription. KMT2D is a key regulator of gene expression during development and differentiation. Mutations in KMT2D are a major cause of Kabuki syndrome and are frequently found in various cancers, including lymphomas and medulloblastoma. The protein contains multiple domains, including a SET domain responsible for methyltransferase activity, PHD fingers, and a LXXLL motif, and it functions as part of a large complex (COMPASS-like) that regulates transcriptional activation.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Kabuki syndrome 1 | Heterozygous loss-of-function mutations (nonsense, frameshift, splice site) lead to haploinsufficiency, disrupting H3K4 methylation and gene expression during development. | OMIM #147920; ClinVar; multiple studies |
| Multiple cancers (e.g., lymphomas, medulloblastoma, lung, breast) | Somatic mutations, often loss-of-function, contribute to tumorigenesis by altering gene expression programs that control cell proliferation and differentiation. | COSMIC; ClinVar; literature |
| Neurodevelopmental disorders | De novo mutations in KMT2D are associated with intellectual disability and developmental delay, often overlapping with Kabuki syndrome features. | ClinVar; literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | High | RNA-seq data from GTEx and Human Protein Atlas |
| Lung | Medium | RNA-seq data |
| Liver | Medium | RNA-seq data |
| Kidney | Medium | RNA-seq data |
| Testis | High | RNA-seq data |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (leukemia) | High | Cancer cell line with high expression |
| HeLa (cervical cancer) | Medium | Moderate expression |
| A549 (lung cancer) | Medium | Moderate expression |
| MCF7 (breast cancer) | Low | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg5045Ter | Nonsense | Rare in Kabuki syndrome | Loss of function, truncation |
| p.Gln4475Ter | Nonsense | Rare in Kabuki syndrome | Loss of function, truncation |
| p.Arg5436Gln | Missense | Somatic in cancer | Likely loss of function, altered catalytic activity |
| p.Ser4744Leu | Missense | Somatic in cancer | Uncertain, possibly loss of function |
Mutation functional classification
Loss of Function (LOF)
Most KMT2D mutations in Kabuki syndrome and cancer are loss-of-function, leading to reduced H3K4 methylation and altered gene expression.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well characterized; some missense variants may increase activity but evidence is limited.
Dominant Negative (DN)
Dominant-negative effects are not commonly reported; haploinsufficiency is the primary mechanism.
View complete mutation data：
Gene Ontology (GO)
| • histone-lysine N-methyltransferase activity | • methyltransferase activity |
| • metal ion binding | • zinc ion binding |
| • chromatin binding | • nucleus |
| • regulation of transcription | • DNA-templated |
| • chromatin organization | • cell differentiation |
Pathways
• Histone modification
• Transcriptional regulation by KMT2D
• COMPASS-like complex pathway
Protein Summary
The KMT2D protein is a large (approximately 590 kDa) histone methyltransferase that catalyzes mono-, di-, and tri-methylation of histone H3 at lysine 4 (H3K4me1/2/3). It is a component of the COMPASS-like complex, which is involved in transcriptional activation. KMT2D plays critical roles in embryonic development, hematopoiesis, and neurogenesis. Its activity is regulated by interactions with other proteins and post-translational modifications. Loss of KMT2D function leads to developmental disorders and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| KMT2D Knockout HEK293 Cell Line | EDJ-KQ3122 | Human | 8085 | Details Get a Quote |
| KMT2D Knockout HeLa Cell Line | EDJ-KQ18166 | Human | 8085 | Details Get a Quote |
| KMT2D Knockout HCT 116 Cell Line | EDJ-KQ24478 | Human | 8085 | Details Get a Quote |
| Kmt2d Knockout 4T1 Cell Line | EDJ-KZ316 | Mouse | 381022 | Details Get a Quote |
| Kmt2d Knockout ID8 Cell Line | EDJ-KZ317 | Mouse | 381022 | Details Get a Quote |
| Kmt2d Knockout MC-38 Cell Line | EDJ-KZ318 | Mouse | 8085 | Details Get a Quote |
| KMT2D Knockout A-549 Cell Line | EDJ-KQ63311 | Human | 8085 | Details Get a Quote |
