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KMT2D
lysine methyltransferase 2D
The KMT2D gene provides instructions for an enzyme crucial in regulating gene activity through histone methylation, essential for proper development and linked to Kabuki syndrome. KMT2D, also known as MLL2, encodes a protein that acts as a histone methyltransferase, modifying histones to control gene expression.
KMT2D is located on the long (q) arm of chromosome 12, at band 12q13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
The KMT2D gene, also known by historical names such as MLL2 or MLL4, encodes an enzyme critical for modulating the activity of other genes. This enzyme, lysine-specific methyltransferase 2D, plays a foundational role in human development by influencing gene expression patterns in various tissues and organs throughout the body.
Dysregulation of KMT2D function, primarily through genetic variants, can lead to developmental disorders. Most notably, pathogenic variants in KMT2D are recognised as a significant cause of Kabuki syndrome, a complex genetic condition affecting multiple body systems.
What the gene does
The KMT2D gene provides instructions for synthesising lysine-specific methyltransferase 2D, an enzyme primarily functioning as a histone methyltransferase. Histones are proteins that DNA wraps around to form compact structures called chromosomes. By adding methyl groups to specific histone proteins, KMT2D controls the accessibility of DNA, thereby regulating the activation or silencing of particular genes.
This epigenetic modification orchestrated by KMT2D is crucial for normal development processes, as it precisely controls when and where certain genes are expressed. Research suggests that KMT2D specifically activates genes important for growth and differentiation. Furthermore, the KMT2D protein is understood to function as a tumour suppressor, helping to prevent the uncontrolled cell growth and division characteristic of cancer development.
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Chromosome location
The KMT2D gene is located on chromosome 12, specifically at position 12q13.12. This location refers to the long arm (q) of chromosome 12, within region 13.12. The KMT2D gene is expressed in numerous tissues and organs, underscoring its broad importance in cellular function and development.
Protein structure
The lysine-specific methyltransferase 2D protein, encoded by the KMT2D gene, is an extensive protein composed of 5537 amino acids. Its structural organisation includes several distinct functional domains critical for its enzymatic activity and protein interactions.
Key domains include multiple zinc finger motifs: a C2HC pre-PHD-type 1 degenerate zinc finger (amino acids 104-149), a PHD-type 1 zinc finger (amino acids 170-218), a PHD-type 2 zinc finger (amino acids 226-276), an atypical RING-type 1 zinc finger (amino acids 229-274), a PHD-type 3 zinc finger (amino acids 273-323), and a degenerate RING-type 2 zinc finger (amino acids 276-321). The protein also features several disordered regions, such as those at amino acids 1-60, 368-387, 393-416, and a large region from 436-1331. Within the larger disordered region, there are 15 repeats of S/P-P-P-E/P-E/A, exemplified by specific repeats at amino acids 442-446, 460-464, 469-473, and 496-500. These diverse domains contribute to the protein's ability to bind DNA and regulate gene expression.
Key variants
Genetic variants within the KMT2D gene can significantly alter the function of the lysine-specific methyltransferase 2D enzyme. These variants can range from single nucleotide changes that alter a specific amino acid to larger deletions or insertions that may lead to a truncated, non-functional protein. Hundreds of such variants have been identified in individuals with associated health conditions.
While most KMT2D variants linked to developmental disorders are inherited in an autosomal dominant pattern, meaning only one altered copy of the gene is sufficient to cause the condition, individuals can also acquire somatic variants. Somatic variants occur during a person's lifetime and are present only in specific cells, often observed in various cancers, including certain brain tumours and lymphomas.
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.10570C>T | p.Gln3524Ter | Pathogenic | ★★☆☆ | Kabuki syndrome |
c.10621G>C | p.Ala3541Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome |
c.10740+1G>A | - | Pathogenic | ★★☆☆ | Kabuki syndrome |
c.10744C>T | p.Arg3582Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Kabuki syndrome 1 |
c.10784A>G | p.Tyr3595Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Kabuki syndrome 1 |
c.10813C>T | p.Gln3605Ter | Pathogenic | ★★☆☆ | Kabuki syndrome |
c.10999C>T | p.Gln3667Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Kabuki syndrome 1 |
c.11119C>T | p.Arg3707Ter | Pathogenic | ★★☆☆ | Kabuki syndrome 1 |
c.11149C>T | p.Gln3717Ter | Pathogenic | ★★☆☆ | not provided |
c.11263C>T | p.Gln3755Ter | Pathogenic | ★★☆☆ | Kabuki syndrome 1 |
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 variants in the KMT2D gene are primarily associated with Kabuki syndrome, a rare genetic disorder characterised by distinctive facial features, intellectual disability, and a range of other physical abnormalities. The clinical presentation of Kabuki syndrome can vary widely among affected individuals.
Beyond Kabuki syndrome, somatic (non-inherited) variants in KMT2D have been identified in certain types of cancer, indicating a role for the gene in tumour suppression. Additionally, KMT2D is implicated in the development of conditions such as anophthalmia/microphthalmia, coloboma, and bladder cancer.
Inheritance pattern
Conditions caused by pathogenic KMT2D variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the KMT2D gene is widely recognised for its clinical significance within the NHS Genomic Medicine Service. It is included on several Green-rated panels in NHS England's National Genomic Test Directory, meaning there is strong evidence for its association with specific conditions and that testing is routinely offered when clinically indicated.
KMT2D is found on panels covering conditions such as Anophthalmia or microphthalmia, CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), Clefting, Congenital hyperinsulinism (R144), Deafness and congenital structural abnormalities, Foetal anomalies (R21), Foetal hydrops, Holoprosencephaly (R85), Intellectual disability (R29), Intestinal failure or congenital diarrhoea (R331), IUGR and IGF abnormalities, Kabuki syndrome, Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Skeletal dysplasia (R104), and Structural eye disease (R36). Additionally, it is part of the DDG2P panel and the COVID-19 research panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle, including a balanced diet and regular physical activity, generally supports overall health. For individuals with genetic conditions, such as those associated with the KMT2D gene, lifestyle choices can be part of a broader health management plan.
Evidence suggests that general wellness practices can contribute to better health outcomes; however, there is no specific lifestyle intervention known to prevent or directly treat conditions caused by KMT2D variants. Individuals should discuss any lifestyle changes with their healthcare provider.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions caused by variants in the KMT2D gene. The KMT2D gene's role in epigenetic regulation is complex, and intervention through supplements is not established as an effective strategy.
Individuals considering taking any supplements should always consult with a healthcare professional to ensure they are appropriate and safe, especially given potential interactions with existing conditions or medications.
Frequently asked questions
What is the primary function of the KMT2D gene?
The KMT2D gene provides instructions for an enzyme called lysine-specific methyltransferase 2D, which acts as a histone methyltransferase. This enzyme adds methyl groups to histone proteins, thereby regulating gene activity critical for proper development.
What health conditions are associated with KMT2D gene variants?
Pathogenic variants in the KMT2D gene are primarily associated with Kabuki syndrome. Additionally, somatic variants are found in some cancers, and the gene is implicated in conditions like anophthalmia/microphthalmia, coloboma, and bladder cancer.
Is Kabuki syndrome inherited?
Yes, Kabuki syndrome linked to KMT2D variants is typically inherited in an autosomal dominant pattern. This means that a person needs to inherit only one altered copy of the KMT2D gene to develop the condition.
Can lifestyle changes or supplements help with KMT2D-related conditions?
While a healthy lifestyle generally supports well-being, there is no specific lifestyle intervention or dietary supplement conclusively proven to prevent, treat, or alleviate conditions caused by KMT2D gene variants. Any health decisions, including taking supplements, should be discussed with a healthcare professional.
Where is the KMT2D gene located in the human genome?
The KMT2D gene is located on the long arm of chromosome 12, at position 12q13.12. This specific genomic location is where the gene resides within the human genetic blueprint.
References
- Dentici ML, Di Pede A, Lepri FR. Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Archives of disease in childhood. 2015. PMID: 25281733
- Liu S, Hong X, Shen C. Kabuki syndrome: a Chinese case series and systematic review of the spectrum of mutations. BMC medical genetics. 2015. PMID: 25896430
- Micale L, Augello B, Maffeo C. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Human mutation. 2014. PMID: 24633898
- Bögershausen N, Wollnik B. Unmasking Kabuki syndrome. Clinical genetics. 2013. PMID: 23131014
- Parsons DW, Li M, Zhang X. The genetic landscape of the childhood cancer medulloblastoma. Science (New York, N.Y.). 2011. PMID: 21163964
- Paulussen AD, Stegmann AP, Blok MJ. MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Human mutation. 2011. PMID: 21280141
- Natarajan TG, Kallakury BV, Sheehan CE. Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon. Cancer cell international. 2010. PMID: 20433758
- Ng SB, Bigham AW, Buckingham KJ. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature genetics. 2010. PMID: 20711175