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KAT6B
lysine acetyltransferase 6B
The *KAT6B* gene provides instructions for an enzyme involved in modifying histone proteins, which plays a critical role in regulating gene activity during development. The *KAT6B* gene encodes a histone acetyltransferase enzyme that modifies histones, influencing gene expression throughout the body.
KAT6B is located on the long (q) arm of chromosome 10, at band 10q22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The *KAT6B* gene, also known as lysine acetyltransferase 6B, plays a fundamental role in human biology by facilitating the production of a histone acetyltransferase enzyme [PMID:22095279]. This enzyme is critical for modifying histone proteins, which are structural components of chromosomes. By adding acetyl groups to histones, the KAT6B enzyme influences how DNA is packaged and accessed, thereby regulating the activity of various genes.
While the full spectrum of its functions is still under investigation, *KAT6B* is expressed widely across different cells and tissues. Research indicates its particular importance in developmental processes, especially those affecting the skeletal and nervous systems. Dysregulation of *KAT6B* function due to genetic variants can lead to a range of developmental conditions, including Genitopatellar syndrome.
What the gene does
The primary function of the protein produced from the *KAT6B* gene is to act as a histone acetyltransferase. Histones are proteins that associate with DNA to form chromatin, the complex structure that makes up chromosomes. The addition of an acetyl group to specific histone proteins, a process known as histone acetylation, is a key mechanism for regulating gene expression. Acetylation generally leads to a more open chromatin structure, making genes more accessible for transcription.
The KAT6B enzyme works by transferring an acetyl group to lysine residues on histone tails. While the precise molecular targets and regulatory pathways of KAT6B are still being elucidated, it is understood to interact with numerous other proteins within cells. Its role in gene regulation is particularly vital during early development, affecting the proper formation and function of various bodily systems, including the skeleton and the nervous system. Faulty KAT6B activity due to genetic changes can disrupt these delicate developmental processes, leading to the characteristic features of associated conditions [PMID:22095279].
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Chromosome location
The *KAT6B* gene is situated on the long (q) arm of chromosome 10 at band 10q22.2. Chromosome 10 is one of the 23 pairs of chromosomes found in human cells. This specific location indicates its position on the chromosome. The gene spans a significant region of DNA, containing multiple exons that are transcribed and spliced together to form the mature messenger RNA, which then provides the instructions for synthesising the KAT6B protein.
Protein structure
The KAT6B protein is composed of 2073 amino acids. Its structure includes several distinct functional regions and domains that contribute to its role as a histone acetyltransferase. Near its N-terminus, it features a SAMD1-like winged helix (WH) domain, spanning amino acids 1-77, followed by a H15 domain from amino acids 103-176. The protein also contains two PHD-type zinc finger domains: PHD-type 1 (amino acids 213-272) and PHD-type 2 (amino acids 269-320). A significant portion of its enzymatic activity resides within the MYST-type HAT (Histone Acetyltransferase) domain located between amino acids 715-989, which includes a catalytic region from amino acids 718-1008. Within this catalytic area is a C2HC MYST-type zinc finger (amino acids 748-773). A region involved in interaction with BRPF1 is also present from amino acids 752-1008. Additionally, the protein contains several disordered regions, including those at amino acids 72-97, 360-409, 442-531, 553-583, 639-663, and a particularly long one from amino acids 1022-1452. A region negatively regulating HAT activity is also noted across amino acids 361-717.
Key variants
*KAT6B* gene variants encompass a range of genetic changes, including small insertions, deletions, and single nucleotide changes, as well as larger chromosomal rearrangements. These variations can alter the gene's instructions, potentially leading to a dysfunctional or non-functional KAT6B protein. The specific impact of a variant often depends on its location within the gene and the type of change it introduces. Some variants may lead to a complete loss of protein function, while others might impair its ability to interact with other proteins or modify histones effectively, disrupting normal developmental processes.
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.1054C>T | p.Arg352Ter | Pathogenic | ★★☆☆ | KAT6B-related disorder |
c.1061+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2347C>T | p.Arg783Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Blepharophimosis - intellectual disability syndrome, SBBYS type |
c.2960G>A | p.Trp987Ter | Pathogenic/Likely pathogenic | ★★☆☆ | KAT6B-related disorder |
c.3004C>T | p.Arg1002Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.3040C>T | p.Gln1014Ter | Pathogenic | ★★☆☆ | Blepharophimosis - intellectual disability syndrome, SBBYS type |
c.3147G>A | p.Pro1049= | Pathogenic | ★★☆☆ | not provided |
c.3172C>T | p.Arg1058Ter | Pathogenic | ★★☆☆ | not provided |
c.3217G>T | p.Glu1073Ter | Pathogenic | ★★☆☆ | Blepharophimosis - intellectual disability syndrome, SBBYS type |
c.3253del | p.Glu1085fs | Pathogenic | ★★☆☆ | not provided |
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
Variants in the *KAT6B* gene are associated with several inherited conditions, often presenting with overlapping features impacting development. These include Genitopatellar syndrome, an autosomal dominant condition characterised by genital abnormalities, absent or underdeveloped kneecaps, and intellectual disability. Another related condition is the Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome, which shares some clinical features with Genitopatellar syndrome but has distinct developmental abnormalities [PMID:22095279]. Somatic variants in *KAT6B* have also been observed in some cancers, such as uterine leiomyomas.
Inheritance pattern
Conditions caused by pathogenic KAT6B 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 *KAT6B* gene is recognised for its clinical significance within the NHS Genomic Medicine Service. It is included on several PanelApp green lists, indicating sufficient evidence for its association with human disease. These panels include Arthrogryposis (R83), Clefting, DDG2P (Developmental Disorders Genotype-to-Phenotype), Foetal Anomalies (R21), Intellectual Disability (R29), Rare Syndromic Craniosynostosis or Isolated Multisuture Synostosis (R100), and Skeletal Dysplasia (R104). This inclusion highlights the gene's importance in diagnosing and understanding a range of developmental and congenital conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research into the *KAT6B* gene primarily focuses on its molecular and genetic roles in development and disease rather than direct lifestyle interventions. Generally, maintaining a healthy lifestyle, including a balanced diet and regular physical activity, supports overall well-being. However, there is no conclusive evidence to suggest that specific lifestyle choices can prevent the onset or alter the progression of conditions associated with *KAT6B* gene variants. Any health concerns should be discussed with a healthcare professional.
Supplement considerations
There is currently no scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions caused by *KAT6B* gene variants. Individuals considering any supplements should consult with a healthcare professional, as some supplements can interact with medications or have adverse effects. Focus should remain on clinically supported management strategies as advised by medical specialists.
Frequently asked questions
What is the primary function of the KAT6B gene?
The *KAT6B* gene provides instructions for creating a histone acetyltransferase enzyme. This enzyme plays a crucial role in modifying histone proteins by adding acetyl groups, which helps regulate gene activity, especially during early development.
Which conditions are associated with variants in the KAT6B gene?
Variants in the *KAT6B* gene are linked to several developmental conditions, including Genitopatellar syndrome and the Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome. These conditions often affect skeletal development, intellectual abilities, and other systems.
Is KAT6B associated with cancer?
Yes, somatic genetic changes involving the *KAT6B* gene, such as chromosomal rearrangements, have been identified in certain types of cancer. These changes are acquired during a person's lifetime and are present only in specific cells, such as in uterine leiomyomas.
How is the KAT6B gene relevant in the UK's NHS Genomic Medicine Service?
The *KAT6B* gene is listed on several NHS PanelApp green lists, indicating its established role in various conditions. This includes panels for Arthrogryposis, Clefting, Intellectual Disability, and Skeletal Dysplasia, making it a focus for genetic testing and diagnosis in the UK.
Can lifestyle changes or supplements help manage KAT6B-related conditions?
There is currently no scientific evidence to support that specific lifestyle changes or dietary supplements can prevent or treat conditions associated with *KAT6B* gene variants. Management should follow clinical guidance from healthcare professionals.
References
- Campeau PM, Kim JC, Lu JT. Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. American journal of human genetics. 2012. PMID: 22265014
- Simpson MA, Deshpande C, Dafou D. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. American journal of human genetics. 2012. PMID: 22265017
- Campeau PM, Lu JT, Dawson BC. The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. Human mutation. 2012. PMID: 22715153
- Clayton-Smith J, O'Sullivan J, Daly S. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. American journal of human genetics. 2011. PMID: 22077973
- Yang XJ, Ullah M. MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells. Oncogene. 2007. PMID: 17694082
- Moore SD, Herrick SR, Ince TA. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer research. 2004. PMID: 15313893
- Kojima K, Kaneda K, Yoshida C. A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13). British journal of haematology. 2003. PMID: 12542485
- Panagopoulos I, Fioretos T, Isaksson M. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Human molecular genetics. 2001. PMID: 11157802
- Champagne N, Bertos NR, Pelletier N. Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. The Journal of biological chemistry. 1999. PMID: 10497217