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BTK
Bruton tyrosine kinase
The BTK gene provides instructions for producing Bruton tyrosine kinase, a protein that plays a critical role in the development and maturation of B cells, which are essential for the body's immune response. The BTK gene is vital for a properly functioning immune system, as the protein it encodes, Bruton tyrosine kinase, is indispensable for the maturation of B cells.
BTK is located on the long (q) arm of chromosome X, at band Xq22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The BTK gene, also known as Bruton tyrosine kinase, is a key component of the human immune system. It encodes a protein vital for the development and maturation of B cells, a type of white blood cell crucial for adaptive immunity. Proper BTK function ensures the body can produce antibodies to fight infections effectively.
Disruptions in the BTK gene can lead to conditions characterised by impaired B cell development and severe antibody deficiencies, making affected individuals highly susceptible to various infections. Its importance in immune health makes it a significant gene in the study of immunodeficiency disorders.
What the gene does
The protein encoded by the BTK gene, Bruton tyrosine kinase, acts as a signalling molecule within B cells. This protein transmits critical biochemical signals that instruct B cells to mature and subsequently produce antibodies. Antibodies are specialised proteins that identify and neutralise foreign invaders like bacteria and viruses.
Without functional BTK protein, B cells cannot mature correctly or produce sufficient antibodies. This deficiency compromises the body's ability to mount an effective immune response against pathogens, leading to increased susceptibility to recurrent and severe infections. The BTK protein is thus fundamental to the development of humoral immunity.
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Chromosome location
The BTK gene is located on the long (q) arm of the X chromosome at position 22.1, specifically at band Xq22.1. It is typically inherited in an X-linked recessive manner, meaning that males are more frequently and severely affected by conditions associated with pathogenic variants in this gene.
Protein structure
The Bruton tyrosine kinase protein consists of 659 amino acids and possesses several distinct functional domains. These include an N-terminal PH domain (amino acids 3-133), which contains an Inositol-(1,3,4,5)-tetrakisphosphate 1-binding region (amino acids 12-24). Following this is a Btk-type Zinc finger domain (amino acids 135-171) and a Disordered region (amino acids 171-210). Further towards the C-terminus are an SH3 domain (amino acids 214-274), an SH2 domain (amino acids 281-377), and a Protein kinase domain (amino acids 402-655). The protein also contains a CAV1-binding motif (amino acids 581-588) within its kinase domain.
Key variants
Variants in the BTK gene can lead to a spectrum of immune system dysfunctions. These genetic changes can range from single amino acid substitutions to larger deletions or insertions, all of which may impair the BTK protein's function. The specific impact of a variant often depends on its location within the gene and the resulting alteration to the protein's structure or activity.
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.182T>A | p.Ile61Asn | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.1834C>T | p.Gln612Ter | Pathogenic | ★★☆☆ | X-linked agammaglobulinemia |
c.423del | p.Lys141fs | Pathogenic | ★★☆☆ | X-linked agammaglobulinemia |
c.1300G>T | p.Glu434Ter | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.1428_1429del | p.Met477fs | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.1545del | p.Lys515fs | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.425dup | p.Tyr142Ter | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.862C>G | p.Arg288Gly | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia |
c.908del | p.Gly303fs | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
c.931A>T | p.Lys311Ter | Pathogenic | ★☆☆☆ | X-linked agammaglobulinemia with growth hormone deficiency |
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 BTK gene are primarily associated with X-linked agammaglobulinaemia (Bruton), also referred to as X-linked agammaglobulinaemia (AR). This condition is characterised by a profound deficiency or absence of mature B cells, leading to a severe lack of antibodies and recurrent bacterial infections. Additionally, some BTK variants have been linked to isolated growth hormone deficiency, which includes symptoms such as slow growth, short stature, and a weakened immune response.
- X-linked agammaglobulinaemia Dedicated page coming soon
- X-linked agammaglobulinaemia (Bruton) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic BTK variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
In the UK, the BTK gene is included on several NHS national genomic testing panels, indicating its recognised clinical significance. It is part of the 'Agammaglobulinaemia with absent BTK expression' (R233) and 'Primary immunodeficiency or monogenic inflammatory bowel disease' (R15) panels. Furthermore, it is assessed within the 'COVID-19 research' panel and the 'Infantile enterocolitis & monogenic inflammatory bowel disease' panel, as well as the 'Pituitary hormone deficiency' (R159) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the BTK gene?
The BTK gene provides instructions for the Bruton tyrosine kinase protein, which is essential for the normal development and maturation of B cells. These B cells are crucial for producing antibodies that fight infections.
What conditions are associated with BTK gene variants?
Variants in the BTK gene are primarily linked to X-linked agammaglobulinaemia (Bruton), a severe immune deficiency. Some variants have also been associated with isolated growth hormone deficiency, affecting growth and immune function.
How is the BTK gene inherited?
The BTK gene is located on the X chromosome, meaning it has an X-linked inheritance pattern. This typically results in males being more commonly and severely affected by BTK-related conditions.
References
- Wit JM, Kiess W, Mullis P. Genetic evaluation of short stature. Best practice & research. Clinical endocrinology & metabolism. 2011. PMID: 21396571
- Alatzoglou KS, Dattani MT. Genetic causes and treatment of isolated growth hormone deficiency-an update. Nature reviews. Endocrinology. 2010. PMID: 20852587
- Jyonouchi H, Geng L, Törüner GA. Monozygous twins with a microdeletion syndrome involving BTK, DDP1, and two other genes; evidence of intact dendritic cell development and TLR responses. European journal of pediatrics. 2008. PMID: 17520285
- Conley ME, Farmer DM, Dobbs AK. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clinical and experimental immunology. 2008. PMID: 18241230
- Sedivá A, Smith CI, Asplund AC. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. Journal of clinical immunology. 2007. PMID: 17851739
- Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clinical immunology (Orlando, Fla.). 2006. PMID: 16297664
- Väliaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Human mutation. 2006. PMID: 16969761
- Richter D, Conley ME, Rohrer J. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2001. PMID: 11338284
- Maas A, Hendriks RW. Role of Bruton's tyrosine kinase in B cell development. Developmental immunology. 2001. PMID: 11785667
- Adam MP, Bick S, Mirzaa GM. X-Linked Agammaglobulinemia. 1993. PMID: 20301626