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|Coordinate||63,384,002 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||B lymphoid kinase|
|Chromosomal Location||63,372,837-63,417,187 bp (-)|
|MGI Phenotype||Homozygous mutation of this gene does not result in a phenotype.|
|Amino Acid Change||Serine changed to Proline|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000014597]|
AA Change: S93P
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||increase in IgE response to a Cysteine Protease (Papain), increase in total IgE level|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||01/06/2017 11:15 AM by Anne Murray|
|Record Created||11/10/2015 11:04 AM by Tao Yue|
The blaenka phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R3719, some of which showed increased levels of IgE in the serum (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 31 mutations. The IgE phenotype was linked to a mutation in Blk: a T to C transition at base pair 63,384,002 (v38) on chromosome 14, or base pair 33,186 in the GenBank genomic region NC_000080 encoding Blk. Linkage was found with a recessive model of inheritance, wherein five variant homozygotes departed phenotypically from 22 homozygous reference mice and 23 heterozygous mice with a P value of 1.033 x 10-4 (Figure 2).
The mutation corresponds to residue 697 in the NM_007549 mRNA sequence in exon 5 of 13 total exons.
The mutated nucleotide is indicated in red. The mutation results in a serine (S) to proline (P) substitution at position 93 (S93P) in the BLK protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.000).
Blk is a member of the Src family of tyrosine kinases (SFKs), which also includes Src, Yes, Fgr, Fyn, Lck (see the record for iconoclast), Hck, Lyn (see the record for Lemon), and Yrk (1). The members of the SFKs share highly conserved domains including a Src-homology 3 (SH3) domain (amino acids 52-112 in Blk), an SH2 domain (amino acids 118-214), a tyrosine kinase domain (amino acids 235-488), and a C-terminal regulatory region [Figure 3; reviewed in (2-4)]. A ‘unique’ domain of 50-70 amino acids between the N-terminus and the SH3 domain varies among the members of the SFKs (4).
The kinase domain has N- and C-terminal lobes that flank an ATP- and substrate- binding cleft [Figure 4; PDB:2SRC; (5;6)]. The N-terminal lobe is involved in anchoring and orienting ATP, while the C-terminal lobe is primarily responsible for substrate binding and initiating phosphotransfer (7). Src family kinases are held in a closed, inactive conformation by intramolecular interactions between a phosphorylated tyrosine in the C-terminal tail and the SH2 domain [Figure 4; (5;6;8)]. This interaction couples the SH2 domain to the C-terminal tail, and also holds the SH2 and SH3 domains in a rigid conformation that disfavors kinase activation (9). In addition to the SH2-C-terminal tail interaction, the closed conformation of Src family kinases is also maintained by the docking of the SH3 domain onto an internal polyproline type II helical sequence formed by the linker between the SH2 and kinase domains (5;6;8). This polyproline helix is sandwiched between the SH3 domain and the back surface of the N-terminal lobe of the catalytic domain. Binding of the SH2 domain to the phosphorylated tail segment has been proposed to be important for correctly positioning the SH2-kinase domain linker for interaction with the SH3 domain. When the activation loop tyrosine (Tyr383 in Blk) is dephosphorylated, the αC helix rotates outward, assuming a conformation unable to coordinate the α- and β-phosphates of ATP within the catalytic cleft. In Lyn, dephosphorylation of the tyrosine by the tyrosine phosphatase CD45 results in a conformation change in Lyn, subsequently promoting Lyn autophosphorylation of Tyr397 and an increase in kinase activity (10). Phosphorylation of the activation loop also increases the accessibility of the SH3 domain for ligands, and it has been proposed that Src activity may generally control the availability of its regulatory domains (11). Together, phosphorylation of the tyrosine in the C-terminal tail and dephosphorylation of the activation loop tyrosine promote a closed, inactive conformation in which the lobes of the kinase domain are closely apposed and the αC helix is shifted outwards.
Activated Blk can be ubiquitinated by the E3 ligase E6AP and preferentially degraded by the ubiquitin-proteasome pathway (12).
The blaenka mutation results in a serine (S) to proline (P) substitution at position 93 (S93P). Residue 93 is within the SH3 domain.
The SFKs interact with immune cell receptors, growth factor receptors, integrins, and G protein-coupled receptors to regulate cell migration, adhesion, phagocytosis, cell survival, differentiation, DNA synthesis, and proliferation through the phosphorylation of signaling intermediates (17;18). B cells express several SFKs, including Blk, Lyn, Fyn, Hck, Fgr, and Lck. Following BCR ligation, Blk and/or Lyn phosphorylates the ITAMs of the Igα (see the record for crab)/Igβ BCR subunits [Figure 5; (1;19;20)]. These phosphotyrosines then act as docking sites for the SH2 domains of Syk (see the record for poppy), resulting in Syk phosphorylation and activation. Syk phosphorylates a number of downstream targets including B cell linker (BLNK; see the record for busy), PLCγ2, and protein kinase C β (PKCβ; see the record for Untied). BCR stimulation also activates phosphatidylinositol 3 kinase (PI3K) resulting in the generation of PIP3, which binds selectively to the pleckstrin homology domain of Btk (Bruton’s tyrosine kinase), facilitating membrane recruitment of the kinase. Phosphorylated BLNK also provides docking sites for Btk, as well as PLCγ2, which results in the additional phosphorylation and activation of PLCγ2 by Btk leading to the hydrolysis of phosphatidylinositol-3,4-diphosphate (PIP2) to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (21). The recruitment of Vav1, Nck, and Ras by BLNK to the BCR activates MAP kinase cascades such as JNK, p38 and extracellular signal regulated kinase (ERK) [reviewed in (22)]. Together, these signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for finlay, xander and panr2) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies [reviewed in (23)]. Lyn is essential for the terminal differentiation of peripheral B cells as well as the elimination of autoreactive B cells (24); however, Lyn, Fyn, and Blk have redundant functions in pre-B cell expansion and BCR signaling initiation. Mice deficient in Blk, Fyn, and Lyn exhibit loss of pre-B cell receptor-mediated NF-κB activation as well as a reduction in the frequency of pre-B cells and a reduction in the number of peripheral B cells (25). Together, all three SFKs are required for pre-B cell development. Although functional redundancy is observed in B cell development and activation, Blk is required for the development and function of marginal zone B cells (26). In addition, Blk is required for early T cell development and in the development and function of γδ-17 cells (14). In leukemia stem cells, Blk functions as a tumor suppressor through a pathway that involves Pax5 (see the record for Apple) and p27, but does not affect normal hematopoietic stem cells (27). Other studies have shown that Blk may function as an oncogene (28). Blk promoted the proliferation of malignant T cells from cutaneous T-cell lymphoma patients (29).
Blk-deficient (Blk-/-) mice do not have an overt immunological phenotype (30), but the mice displayed slight changes in B cell differentiation and activation (26;31). The Blk-/- mice had an increased frequency of splenic B cells and preplasmablasts than wild-type littermates (31). Blk-/- mice exhibited higher amounts of anti-dsDNA IgG antibodies with age compared to wild-type littermates and developed immune complex-mediated glomerulonephritis (32). Blk-/- mice had increased numbers of splenic B1a cells; the B1a cells subsequently differentiated into class-switched CD138+IgG-secreting B1a cells (32). Blk-/- mice had reduced numbers of marginal zone B cells but increased responses to BCR stimulation compared to wild-type littermates (26). The B cell hyperactivity subsequently led to the development of autoimmunity by 6-months of age, including increased numbers of marginal zone and B1 B cells and increased levels of serum anti-nuclear antibodies. The Blk+/−.lpr mouse model expresses Blk at low levels. Reducing Blk expression resulted in increased secretion of proinflammatory cytokines and the development of proteinuria, and kidney disease (31).
Mutations in human BLK have been linked to several disorders. Mutations that lead to reduced Blk expression are linked to increased susceptibility to systemic lupus erythematosus (SLE) through the dysregulation of the expression of proinflammatory cytokines (33). In addition to SLE, mutations in BLK are linked to other autoimmune disorders including rheumatoid arthritis (34), dermatomyositis (35), systemic sclerosis (36), and Sjögren's syndrome (37). Paitents with the rheumatoid artritis-causing BLK mutations have lower basal BCR activity, but the B cells are hyperactivatable (38). In addition, the patients exhibit upregulation of CD86 after BCR crosslinking and enhanced T cell stimulatory capacity (38). Simpfendorer and colleagues propose that the increased levels of CD86 correlates with an increased ability to induce T cell activation. The rheumatoid arthritis patients also have increased numbers of isotype-swithced memory B cells (e.g., IgD+ single-positive switched memory B cells). Mutations in BLK have also been linked to Kawasaki disease in Taiwanese, Japanese, Korean, and European populations (39-41). Kawasaki disease is a vasculitis that affect primarily infants and young children (42). Kawasaki patients have prolonged fevers and can exhibit variable skin rash, bilateral conjunctival injection, erythema of the oral mucosa, lips, tongue, palms of the hands, and soles of the feet, and cervical lymphadenopathy. Approximately a quarter of the Kawasaki disease patients develop coronary artery aneurysms. A mutation in BLK has been linked to common variable immunodeficiency (CVID), which is chachterized by defective generation of high-affinity antibodies (43). Patients with CVID have an increased risk of recurrent infections of the respiratory and intestinal tract. The BLK mutation linked to CVID causes diminished B cell proliferation and decreased ability of B cells to elicit antigen-specific CD4+ T-cell responses (43). Mutations in BLK are linked to type 11 maturity-onset diabetes of the young (MODY; OMIM: #613375), a subset of diabetes that has a young age of onset (usually before the age of 25) (13). BLK may regulate insulin levels in response to glucose. BLK overexpression increased insulin secretion in cases of high glucose concentraitons; loss of BLK expression resulted in reduced insulin secretion in cases of high glucose (13). In low glucose, BLK overexpression or downregulation did not significantly affect insulin secretion. BLK also enhances the expression of β-cell transcription factors Pdx-1 and Nkx6.1. Reduced BLK expression is linked to childhood acute lymphoblastic leukemia (44).
The phenotype observed in the blaenka mice indicates loss of Blkblaenka function and a possible reduction in BCR-mediated B cell activation. Changes in the frequencies of B and T cell populations in the peripheral blood was not observed in the blaenka mice, indicating that some residual Blk function (or compensation by other SFKs may occur).
blaenka(F):5'- TCCCTTGGCATCATTCAGAG -3'
blaenka(R):5'- ACCTCCTTATCACCAGGCTG -3'
blaenka_seq(F):5'- GAGAGCCAGAACTTTCCATTCCTG -3'
blaenka_seq(R):5'- ACCAGGCTGTCTGTCTGTC -3'
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|Science Writers||Anne Murray|
|Authors||Tao Yue and Bruce Beutler|
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