Alternative titles; symbols
HGNC Approved Gene Symbol: BLK
SNOMEDCT: 609578001;
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:11,494,387-11,564,599 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | Maturity-onset diabetes of the young, type 11 | 613375 | Autosomal dominant | 3 |
The BLK gene encodes B-lymphoid tyrosine kinase, a member of the Src family of tyrosine kinases that phosphorylates the Ig-alpha (CD79A; 112205) subunit of B-cell receptor (BCR) signaling, leading to B-cell activation and clonal expansion (summary by Compeer et al., 2015).
Dymecki et al. (1990) reported the specific expression of a novel tyrosine kinase gene, Blk, in B lymphocytes of the mouse. They demonstrated that the gene is a member of the SRC family of protooncogenes and concluded, on the basis of its preferential expression in B-lymphoid cells, that it functions in a signal transductory pathway specific to this lineage.
Islam et al. (1995) reported the molecular cloning of the human BLK gene and its expression. The BLK gene is a nonreceptor protein tyrosine kinase with a calculated molecular mass of about 58 kD. It has an overall amino acid identity of approximately 87% to the mouse Blk; however, in the unique domain of Src family members (see 190090) there is only 58% homology and an insertion of 6 amino acids in the N-terminal region. The nature of this insertion suggested a functional role in membrane attachment. Islam et al. (1995) did not detect the BLK transcript in nonlymphoid tissues examined. In contrast, expression of murine Blk in plasma cells and T lymphocytes had not been reported. They detected transcripts in human embryonic liver as early as 7.5 weeks of gestation, before the rearrangement of the immunoglobulin heavy-chain gene locus (147100). Furthermore, they detected transcripts in human thymocytes and not in mature T cells. Southern blot analysis revealed polymorphism of this gene in a Caucasian population but not in a Gambian population, indicating a recent origin of this polymorphism. Expression of BLK in immature T cells suggested that it may play an important role in thymopoiesis.
Drebin et al. (1995) likewise cloned the human homolog of murine Blk. The protein predicted by the open reading frame of the cDNA had 505 amino acids with SH3, SH2, and catalytic domains that contained consensus sequences of the SRC protein tyrosine kinase family. Like the murine Blk gene, human BLK is expressed only in B lymphocytes.
In contrast to the results of Drebin et al. (1995), Appel et al. (2002) detected transcription of BLK in lymphoblastoid cell lines, spleen, liver, leukocytes, ovary, muscle, and testis. Mutation screening of each exon by direct sequencing of genomic DNA from KWE patients did not reveal any pathogenic mutation. Because BLK is a member of the SRC family, which is thought to play an important role in the signaling pathways controlling cell proliferation and differentiation, the authors considered the gene to be a good positional candidate for the cancers mapping to this region.
Using RT-PCR, Borowiec et al. (2009) demonstrated that BLK is expressed in human pancreatic islets, and noted a stronger hybridization signal with RNA isolated from microdissected beta cells than for whole islets. Staining of a human tissue array with an anti-BLK antibody confirmed the microarray findings. In addition to lymphatic organs, BLK immunoreactivity was detected in pancreatic islets, striated ducts of salivary glands, hair follicles, and Leydig cells. In islets, BLK colocalized with insulin, indicating selective expression in this cell type.
Appel et al. (2002) determined that the BLK gene contains 13 exons spanning about 70 kb.
By a study of intersubspecies backcrosses, Kozak et al. (1991) mapped the Blk gene to mouse chromosome 14.
By fluorescence in situ hybridization and somatic cell hybrid analysis, Islam et al. (1995) mapped the BLK gene to 8p23-p22. This region is homologous to the region of chromosome 14 carrying the mouse Blk locus.
Drebin et al. (1995) mapped the human BLK gene to chromosome 8p23-p22 by isotopic in situ hybridization.
Appel et al. (2002) constructed a physical and transcription map of the critical region for keratolytic winter erythema (KWE; 148370), an autosomal dominant skin disorder mapped to chromosome 8p23-p22. The BLK gene was identified in the BAC contig between microsatellite markers D8S1695 and D8S1759.
To examine the effects of BLK on insulin secretion and synthesis, Borowiec et al. (2009) overexpressed or knocked down BLK in MIN6 beta cells, and found that in a low-glucose environment, neither BLK overexpression or its downregulation had significant effects on insulin secretion. However, at high glucose concentrations, BLK overexpression significantly enhanced insulin secretion, whereas the opposite effect was noted in cells in which BLK had been downregulated. The enhancement of insulin secretion induced by BLK overexpression was accompanied by a 70% increase in insulin content as compared with control cells. Borowiec et al. (2009) also observed upregulation of the transcription factors PDX1 (600733) and NKX6.1 (602563) in cells overexpressing BLK; this response appeared to be specific because other transcription factors previously reported to modify insulin transcription such as FOXA2 (600288), HNF1A (142410), and HNF4A (600281) were unchanged.
Maturity-Onset Diabetes of the Young
In 3 families with maturity-onset diabetes of the young (MODY11; 613375), Borowiec et al. (2009) identified 5 sequence variations in or near the BLK gene that cosegregated with diabetes (191305.0001-191305.0005), 3 of which occurred together as a haplotype in 1 family (191305.0001-191305.0003). In reporter gene experiments, all mutated forms were associated with a 60 to 80% decrease in luciferase expression with respect to both control and wildtype constructs. None of the family members carrying BLK mutations reported a history of systemic lupus erythematosus (SLE; 152700) or other autoimmune disorders.
Associations Pending Confirmation
In a large genomewide association study of individuals with systemic lupus erythematosus (SLE) and controls, Hom et al. (2008) identified association with a single-nucleotide polymorphism (SNP), rs13277113, lying between BLK and the neighboring C8ORF13 (610085) gene; see SLEB12, 612254. Homozygosity for the risk allele A was associated with decreased expression of BLK mRNA relative to homozygosity for the G allele.
For discussion of a possible association between variation in the BLK gene and susceptibility to rheumatoid arthritis, see 180300.
For discussion of a possible association between variation in the BLK gene and common variable immunodeficiency (see, e.g., CVID1; 607594), see 191305.0006.
SYK (600085) controls pre-B cell development but does not affect NFKB (164011) induction. Saijo et al. (2003) showed that mice triple-deficient in the Src family protein tyrosine kinases (SFKs) Blk, Fyn (137025), and Lyn (165120), but not single-deficient or Syk-deficient mice, had impaired Nfkb induction and B-cell development. The impairment of Nfkb induction could be overcome by protein kinase C-lambda (see 176982) activation. Saijo et al. (2003) suggested that there are 2 separate pathways in pre-B cell receptor signaling, one SFK-dependent and the other SYK-dependent, that contribute critically to pre-B cell development.
Using BCR-ABL (see 151410)-induced chronic myeloid leukemia as a disease model for cancer stem cells, Zhang et al. (2012) showed that BCR-ABL downregulates the Blk gene through c-Myc in leukemic stem cells in chronic myeloid leukemia (CML; see 608232) mice, and that Blk suppresses leukemic stem cell function through a pathway involving an upstream regulator, Pax5 (167414), and a downstream effector, p27 (600778). Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells.
In affected members of a 5-generation Caucasian family (designated 'F8') segregating autosomal dominant maturity-onset diabetes of the young (MODY11; 613375), Borowiec et al. (2009) identified 3 mutations in the BLK gene that occurred together as a haplotype: a G-to-A transition at chr8:11,442,985 in exon 4, resulting in an ala71-to-thr (A71T) substitution; a T-to-G transversion at chr8:11,459,364, at the end of the 3-prime untranslated region (UTR); and a C-to-T transition at chr8:11,468,050, 18 kb from the gene on the 3-prime side. All nucleotide positions are designated according to NCBI36/hg18. The F8 haplotype was also found in 2 (0.003) of 672 Caucasian nondiabetic controls. All 3 mutations decreased in vitro promoter activity in reporter gene experiments; studies in MIN6 beta cells showed that the A71T mutant attenuated the enhancing effect of BLK on insulin content and secretion to the point of being undetectable, and the inducing effect of BLK on the expression of transcription factors PDX1 (600733) and NKX6.1 (602563) was abolished. Noting that the penetrance of the F8 haplotype was 0.33 (2 affected out of 6) among carriers with a body mass index (BMI) less than 28 compared to 0.89 (8 affected out of 9) among carriers with a BMI greater than or equal to 28, Borowiec et al. (2009) suggested that the diabetogenic environment conferred by an increased body weight might be necessary for translation of the beta-cell abnormalities caused by the F8 haplotype into diabetes.
See 191305.0001 and Borowiec et al. (2009). Nucleotide position designated according to NCBI36/hg18.
See 191305.0001 and Borowiec et al. (2009). Nucleotide position designated according to NCBI36/hg18.
In affected members of a 3-generation African American family segregating autosomal dominant maturity-onset diabetes of the young (MODY11; 613375), Borowiec et al. (2009) identified a G-to-A transition at chr8:11,369,157, located 20-kb 5-prime of the transcription start site. The mutation, which was not found in 1,154 nondiabetic African American controls, significantly decreased in vitro promoter activity in reporter gene experiments compared to wildtype. Nucleotide position designated according to NCBI36/hg18.
In affected members of a 4-generation Caucasian family segregating autosomal dominant maturity-onset diabetes of the young (MODY11; 613375), Borowiec et al. (2009) identified a G-to-T transition at chr8:11,459,531, located immediately 3-prime of the polyadenylation signal. The mutation, which was not found in 672 nondiabetic Caucasian controls, significantly decreased in vitro promoter activity in reporter gene experiments compared to wildtype. One family member carried the mutation but did not express abnormal glucose tolerance at 10 years of age. Nucleotide position designated according to NCBI36/hg18.
This variant is classified as a variant of unknown significance because its contribution to common variable immunodeficiency (see, e.g., CVID1; 607594) has not been confirmed.
In a Dutch father and son with recurrent respiratory infections since early childhood and mild hypogammaglobulinemia consistent with CVID, Compeer et al. (2015) identified a heterozygous c.8T-C transition (c.8T-C, NM_001715.2) in the BLK gene, resulting in a leu3-to-pro (L3P) substitution. The variant, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was not found in healthy family members. The variant was not present in the dbSNP or Dutch population-specific GoNL databases. Patient peripheral blood B cells showed normal BLK mRNA and protein levels, suggesting that the variant may cause a functional defect. Patient B cells showed a delayed response and a 50% reduction in phosphorylation of Syk (600085) in response to BCR crosslinking compared to controls. (Syk phosphorylation is the immediate downstream consequence of BLK-mediated phosphorylation of Ig-alpha). Surface expression of B-cell coreceptor molecules in patient cells was similar to controls. B-cell lines expressing the L3P variant also showed defects in Syk phosphorylation after crosslinking and had decreased B-cell proliferation compared to controls. The findings suggested that the L3P variant negatively affects tonic signaling-dependent B-cell proliferation, which may cause hypogammaglobulinemia. Further detailed in vitro functional studies showed that the L3P variant altered endosomal routing of BCR-antigen complexes and caused faster degradation of these complexes, which was associated with impaired activation of CD4+ T cells, likely due to decreased BCR-mediated antigen presentation. These findings elucidated a role for human BLK in BCR signaling, antigen processing, and class II MHC presentation by B cells. The proband was a 7-year-old boy with a history of severe recurrent pulmonary infections since 8 months of age. Laboratory studies showed mild hypogammaglobulinemia, slightly reduced memory B-cell numbers, and impaired responses to certain vaccinations. There were no signs of autoimmunity or lymphoproliferative disease. His father also had a history of recurrent respiratory tract infections and bacteremia associated with small skin lesions. Laboratory studies showed mild hypogammaglobulinemia. The findings were consistent with a clinical diagnosis of CVID.
Hamosh (2024) noted that the L3P variant was present in gnomAD (v4.0) in 46 of 1,613,558 alleles, in heterozygous state only, for a frequency of 2.85 x 10(-5).
Appel, S., Filter, M., Reis, A., Hennies, H. C., Bergheim, A., Ogilvie, E., Arndt, S., Simmons, A., Lovett, M., Hide, W., Ramsay, M., Reichwald, K., Zimmermann, W., Rosenthal, A. Physical and transcriptional map of the critical region for keratolytic winter erythema (KWE) on chromosome 8p22-p23 between D8S550 and D8S1759. Europ. J. Hum. Genet. 10: 17-25, 2002. [PubMed: 11896452] [Full Text: https://doi.org/10.1038/sj.ejhg.5200750]
Borowiec, M., Liew, C. W., Thompson, R., Boonyasrisawat, W., Hu, J., Mlynarski, W. M., El Khattabi, I., Kim, S.-H., Marselli, L., Rich, S. S., Krolewski, A. S., Bonner-Weir, S., Sharma, A., Sale, M., Mychaleckyj, J. C., Kulkarni, R. N., Doria, A. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc. Nat. Acad. Sci. 106: 14460-14465, 2009. [PubMed: 19667185] [Full Text: https://doi.org/10.1073/pnas.0906474106]
Compeer, E. B., Janssen, W., van Royen-Kerkhof, A., van Gijn, M., van Montfrans, J. M., Boes, M. Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help. Oncotarget 6: 10759-10771, 2015. [PubMed: 25926555] [Full Text: https://doi.org/10.18632/oncotarget.3577]
Drebin, J. A., Hartzell, S. W., Griffin, C., Campbell, M. J., Niederhuber, J. E. Molecular cloning and chromosomal localization of the human homologue of a B-lymphocyte specific protein tyrosine kinase (blk). Oncogene 10: 477-486, 1995. [PubMed: 7845672]
Dymecki, S., Niederhuber, J., Desiderio, S. Specific expression of a novel tyrosine kinase gene, Blk, in B lymphoid cells. Science 247: 332-336, 1990. [PubMed: 2404338] [Full Text: https://doi.org/10.1126/science.2404338]
Hamosh, A. Personal Communication. Baltimore, Md. 02/26/2024.
Hom, G., Graham, R. R., Modrek, B., Taylor, K. E., Ortmann, W., Garnier, S., Lee, A. T., Chung, S. A., Ferreira, R. C., Pant, P. V. K., Ballinger, D. G., Kosoy, R., and 15 others. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. New Eng. J. Med. 358: 900-909, 2008. [PubMed: 18204098] [Full Text: https://doi.org/10.1056/NEJMoa0707865]
Islam, K. B., Rabbani, H., Larsson, C., Sanders, R., Smith, C. I. E. Molecular cloning, characterization, and chromosomal localization of a human lymphoid tyrosine kinase related to murine Blk. J. Immun. 154: 1265-1272, 1995. [PubMed: 7822795]
Kozak, C. A., Dymecki, S. M., Niederhuber, J. E., Desiderio, S. V. Genetic mapping of the gene for a novel tyrosine kinase, Blk, to mouse chromosome 14. Genomics 9: 762-764, 1991. [PubMed: 2037301] [Full Text: https://doi.org/10.1016/0888-7543(91)90372-l]
Saijo, K., Schmedt, C., Su, I., Karasuyama, H., Lowell, C. A., Reth, M., Adachi, T., Patke, A., Santana, A., Tarakhovsky, A. Essential role of Src-family protein tyrosine kinases in NF-kappa-B activation during B cell development. Nature Immun. 4: 274-279, 2003. [PubMed: 12563261] [Full Text: https://doi.org/10.1038/ni893]
Zhang, H., Peng, C., Hu, Y., Li, H., Sheng, Z., Chen, Y., Sullivan, C., Cerny, J., Hutchinson, L., Higgins, A., Miron, P., Zhang, X., Brehm, M. A., Li, D., Green, M. R., Li, S. The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nature Genet. 44: 861-871, 2012. [PubMed: 22797726] [Full Text: https://doi.org/10.1038/ng.2350]