BTK
protein-codingBruton tyrosine kinase, the group of SH2 domain containing|Pleckstrin homology domain containing|Tec family tyrosine kinases
Gene summary
The protein encoded by this gene plays a crucial role in B-cell development. Mutations in this gene cause X-linked agammaglobulinemia type 1, which is an immunodeficiency characterized by the failure to produce mature B lymphocytes, and associated with a failure of Ig heavy chain rearrangement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]
- AGMX1
- IMD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~41.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010421
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010615
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010421
Submitter: ClinGen
Bruton-type agammaglobulinemia, or X-linked agammaglobulinemia (XLA) was the first immunodeficiency to be described (Burton,1952). The relationship of BTK to XLA was first reported in 1993 (PMIDs: 8425221, 8380905). Btk is a tyrosine kinase, which is critical in the maturation of Pre-B cells to mature B cells. The absence of functional Btk leads to failure of B-cell development that incapacitates antibody production in XLA patients leading to recurrent bacterial infections (reviewed in PMID: 26909497). Over 900 unique variants have been reported in humans (BTKbase; PMID: 16969761), including missense, nonsense, frameshift, splicing, small indels, and gross insertions or deletions. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Twenty-three unique variants from 23 probands in 4 publications were curated (PMIDs: 8380905, 17765309, 7880320, 8162056). Variants in this gene segregated with disease in 8 additional family members (PMIDs: 17765309, 8162056). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by its role as a tyrosine kinase in B-cell development (PMID: 11606584) and its expression in relevant cells and tissues (PMID: 8380905), both of which are altered in patient cells (PMID: 8425221). Further support is provided by chimeric mice (PMID: 7552995), the xid mouse model (PMID: 8332900), and a null mouse model (PMID: 7552994), all of which recapitulate features of XLA. In summary BTK is definitively associated with x-linked Bruton-type agammaglobulinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in isolated growth hormone deficiency type III (MONDO:0010615). This has been assessed separately given the lack of known overlapping molecular mechanism and distinct phenotype. Furthermore, somatic variants in BTK are associated with malignancy, which is not considered here.
Inheritance Pattern: XL
Disease ID:MONDO:0018967
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010421
Submitter: Myriad Women's Health
Inheritance Pattern: XL
Disease ID:MONDO:0010421
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010615
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010615
Submitter: ClinGen
BTK was first reported in relation to x-linked isolated growth hormone deficiency type III in 1994 (Conley ME, et al., 1994, PMID: 7849697; Duriez B, et al., 1994, PMID: 8013627 ). Isolated growth hormone deficiency type III is characterized by agammaglobulinemia and markedly reduced numbers of B cells, short stature, delayed bone age, and good response to treatment with growth hormone (Conley ME, et al., 1991, PMID: 1880652). The disease was originally described by Fleisher et al., 1980 (PMID: 7189577), however no association with BTK was made in those patients or the subsequent patient described by Monafo et al., 1991 (PMID: 1872183). Furthermore, Stewart et al. (2008) provided an update on the family initially described by Fleisher et al. (1980), finding normal expression and autokinase activity. As such BTK was not considered to be causative of the X-linked hypogammaglobulinemia and isolated growth hormone deficiency observed in this family and an alternate candidate gene, ELF4, was identified with a single Ser369Pro missense variant identified segregating with disease. In BTK, three unique variants (one missense, one nonsense, and one intronic) have been identified in three male probands in two publications (PMIDs: 7849697 and 8013627). This gene-disease association is supported by experimental evidence consistent with the agammaglobulinemia observed in these patients including the role of BTK as a tyrosine kinase in B-cell development (PMID: 11606584) and its expression in relevant cells and tissues (PMID: 8380905), as well as chimeric mice (PMID: 7552995), the xid mouse model (PMID: 8332900), and a null mouse model (PMID: 7552994), all of which recapitulate features of XLA. However, no experimental evidence supporting a relationship with the isolated growth hormone deficiency has been reported and no convincing genetic evidence has emerged relating BTK to the isolated growth hormone deficiency since it was last reported in 1994. In summary, the evidence supporting the relationship between BTK and x-linked isolated growth hormone deficiency type III has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role BTK plays in this disease. Of note, this gene has also been implicated in Bruton-type agammaglobulinemia (MONDO:0010421), which has been assessed separately.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Endocrine
Intervention: Allergy/Immunology/Infectious; Endocrine
Rationale: Antiinfectious prophylaxis, including gammaglobulins, sometimes with prophylactic antibiotics and early and aggressive treatment of infections may be beneficial; Live viral vaccines should be avoided; Recognition and treatment of growth hormone deficiency may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BTK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000061.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 22 | 102 | 5 | 131 | |
| missense | 47 | 82 | 213 | 16 | 1 | 359 |
| nonsense | 64 | 11 | 8 | 83 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 73 | 16 | 89 | |||
| splice donor/acceptor (+/-2bp) | 38 | 21 | 21 | 80 | ||
| Total | 223 | 134 | 264 | 118 | 6 | 745 |
Highest pathogenic variant AF is 0.0000100168645
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000052.1 | 18 | MANE Select | |
| Ensembl | ENSP00000308176.8 | 18 | MANE Select | |
| RefSeq | NP_001274273.1 | 19 | Standard | |
| RefSeq | NP_001274274.1 | 15 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| btk | Danio rerio | Structure: whole organism Quality: wholly dorsalized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Primary immunodeficiency - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- B cell receptor signaling pathway - Homo sapiens (human)
- Fc epsilon RI signaling pathway - Homo sapiens (human)
- Osteoclast differentiation - Homo sapiens (human)
Biological Process
- positive regulation of type III hypersensitivity
- positive regulation of type I hypersensitivity
- negative regulation of cytokine production
- adaptive immune response
- B cell affinity maturation
Molecular Function
- protein tyrosine kinase activity
- non-membrane spanning protein tyrosine kinase activity
- protein binding
- ATP binding
- phosphatidylinositol-3,4,5-trisphosphate binding
Cellular Component
- nucleus
- cytoplasm
- cytosol
- plasma membrane
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000308731
- Coding exons
- 18
- Length
- 36749
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.04 | 72 | 253 | 0.285 | 0.0000198 | 4359 |
| Missense (PolyPhen) | 11 | 99.524 | 0.11053 | 1683 | ||
| Synonymous | 1.34 | 72 | 87.9 | 0.819 | 0.00000660 | 1186 |
| Loss of Function | 4.99 | 0 | 29.0 | 0.00 | 0.00000211 | 499 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:9012831}.;
- Disease
- DISEASE: X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269|PubMed:10220140, ECO:0000269|PubMed:10612838, ECO:0000269|PubMed:10678660, ECO:0000269|PubMed:7627183, ECO:0000269|PubMed:7633420, ECO:0000269|PubMed:7633429, ECO:0000269|PubMed:7711734, ECO:0000269|PubMed:7809124, ECO:0000269|PubMed:7849006, ECO:0000269|PubMed:7849697, ECO:0000269|PubMed:7849721, ECO:0000269|PubMed:7880320, ECO:0000269|PubMed:7897635, ECO:0000269|PubMed:8013627, ECO:0000269|PubMed:8162018, ECO:0000269|PubMed:8162056, ECO:0000269|PubMed:8594569, ECO:0000269|PubMed:8634718, ECO:0000269|PubMed:8695804, ECO:0000269|PubMed:8723128, ECO:0000269|PubMed:8834236, ECO:0000269|PubMed:9016530, ECO:0000269|PubMed:9260159, ECO:0000269|PubMed:9280283, ECO:0000269|PubMed:9445504, ECO:0000269|PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). {ECO:0000269|PubMed:8013627}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.560
Intolerance Scores
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.986
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |