Alternative titles; symbols
HGNC Approved Gene Symbol: CSF2RB
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:36,913,628-36,940,439 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Surfactant metabolism dysfunction, pulmonary, 5 | 614370 | Autosomal recessive | 3 |
The CSF2RB gene encodes the high-affinity beta subunit of a receptor for interleukin-5 (IL5R; 147851), granulocyte-macrophage CSF (CSF2R; 306250) (Tavernier et al., 1991), and interleukin-3 (IL3RA; 308385) (Kitamura et al., 1991).
See also the low-affinity alpha subunit of the receptor (CSF2RA; 306250)
Hayashida et al. (1990) isolated cDNA clones corresponding to the beta subunit of the GMCSF receptor from a human erythroleukemia cDNA library. The deduced 897-amino acid protein had a molecular mass of approximately 120 kD and shares 56% sequence identity with the mouse AIC2B protein.
In the mouse, 2 distinct but related genes, AIC2A (Csf2rb2) and AIC2B (Csf2rb1), encode the beta subunit common to Csf2r, Il5r, and Il3r (Gorman et al., 1992). Hara and Miyajima (1992) stated that the mouse AIC2B gene encodes a common beta subunit for the mouse Gmcsf and Il5 receptors, whereas AIC2A encodes a low-affinity Il3-binding protein by itself. Hara and Miyajima (1992) found that AIC2A formed a high-affinity Il3-binding protein when coexpressed with a mouse protein homologous to the human alpha subunit. In addition, AIC2B formed a high-affinity Il3-binding protein when coexpressed with the alpha subunit. Thus, the mouse has 2 high-affinity Il3 receptors, but only the AIC2B gene encodes a common beta subunit for the mouse Gmcsf, Il5, and Il3 receptors. Robb et al. (1995) referred to the mouse AIC2B gene as 'beta-c' (for common) and the AIC2A gene as 'beta-Il3.'
Shen et al. (1992) mapped the human CSF2RB gene to chromosome 22 by PCR analysis of a series of human/rodent somatic cell hybrids. By fluorescence in situ hybridization to normal human chromosomes and 2 translocations involving chromosome 22 as well as the chromosome expressing the rare fragile site FRA22A, they regionalized the gene to 22q12.2-q13.1, proximal to the fragile site.
Gorman et al. (1992) demonstrated that the 2 mouse genes, provisionally designated Il3rb1 and Il3rb2, are located in the same 250-kb restriction fragment and map to chromosome 5, closely linked to the Sis locus (PDGFB; 190040).
Tavernier et al. (1991) stated that the common receptor subunit, CSF2RB, that is shared between IL5R and CSF2R provides a molecular basis for the observation that IL5 (147850) and CSF2 (138960) can partially interfere with each other's binding and have highly overlapping biologic activities on eosinophils.
D'Andrea et al. (1994) isolated a mutant form of the IL5RB gene from growth factor-independent cells that arose spontaneously after infection of a murine factor-dependent hematopoietic cell line with a retroviral expression construct of the common beta chain gene. The mutation consisted of a 37-amino acid duplication of extracellular sequence that included 2 conserved sequence motifs and conferred ligand-independent growth on the cells. The results suggested that members of the large family of cytokine receptors have the capacity to become oncogenically active.
Jenkins et al. (1995) reported the identification of 2 activating point mutations in the CSF2RB gene that were generated using a PCR-based random mutagenesis procedure. By combining this procedure with a retroviral expression cloning system, they isolated these mutants by virtue of their ability to confer factor independence on a factor-dependent hematopoietic cell line. The ability of point mutations to activate the gene supported the possibility that such mutations could contribute to human leukemia. In addition, the nature and properties of these mutants had important implications for the mechanisms of signaling by the 3 receptors that utilize the common beta subunit. One mutation, val449-to-glu, was located within the transmembrane domain and, by analogy with a similar mutation in the NEU oncogene (164870), might act by inducing dimerization of the common beta subunit. The other mutation, ile374-to-asn, lay in the extracellular, membrane-proximal portion of the common beta molecule.
Dirksen et al. (1998) described expression defects of the CSF2RB and/or the CSF2RA genes in 3 pediatric patients with acute myeloid leukemia (AML) and pulmonary alveolar proteinosis (PAP). Leukemic cells from all 3 patients failed to express express normal levels of beta-c. In addition, leukemic cells from 2 of the patients lacked expression of CSF2RA, as shown by flow cytometry. Strikingly reduced or absent function of beta-c was demonstrated in clonogenic progenitor assays with absent colony-forming unit growth after GMCSF (CSF2; 138960) or IL3 (147740) stimulation. The response to growth factors acting via a growth factor receptor distinct from the GMCSF/IL3/IL5 system was normal. After antileukemic treatment, the pulmonary symptoms resolved and beta-c or beta-c plus CSF2RA expression was normal. Dirksen et al. (1998) concluded that a defect in the CSF2RB and/or CSF2RA on AML blasts can be associated with respiratory failure in patients with AML.
Kondo et al. (2000) showed that a clonogenic common lymphoid progenitor, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B, and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin-2 receptor (146710) and GMCSF receptor. Analysis of mutants of the beta chain of the IL2 receptor revealed that the granulocyte and monocyte differentiation signals are triggered by different cytoplasmic domains, showing that the signaling pathways responsible for these unique developmental outcomes are separable. Finally, Kondo et al. (2000) showed that the endogenous myelomonocytic cytokine receptors for GMCSF and macrophage colony-stimulating factor (CSF1R; 164770) are expressed at low to moderate levels on the more primitive hematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL2 (147680). Kondo et al. (2000) concluded that cytokine signaling can regulate cell fate decisions and proposed that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.
Using yeast 2-hybrid, protein pull-down, and coimmunoprecipitation assays, Kao et al. (2008) showed that CBAP (TMEM102; 613936) interacted with the box-2 motif of beta-c. Removal of GMCSF increased the amount of beta-c and CBAP that immunoprecipitated from TF1 erythroleukemia cells and that colocalized in intracellular compartments. Overexpression of CBAP in IL3 (147740)-dependent Ba/F3 pro-B cells increased the percentage of cells showing mitochondrial changes characteristic of apoptosis and enhanced the apoptotic effect of GMCSF deprivation. Conversely, knockdown of CBAP in TF1 cells reduced cell sensitivity to GMCSF deprivation, but not to other proapoptotic stimuli. Kao et al. (2008) concluded that CBAP binds the isolated beta-c molecule and has a role in GMCSF deprivation-induced apoptosis.
Freeburn et al. (1996) failed to find pathogenic mutations in the CSF2RB gene in 35 patients with acute myeloid leukemia. Although different patterns were detected in 25 (71%) AML patients and 8 (80%) of 10 healthy controls, all nucleotide changes were found to be polymorphisms. The authors concluded that the CSF2RB is highly polymorphic, but point mutations do not appear to contribute to the pathogenesis of AML.
Dirksen et al. (1997) described an expression defect of the CSF2RB gene in 4 of 7 pediatric patients with pulmonary alveolar proteinosis (see SMDP5; 614370). The patients failed to express normal levels of beta-c, as shown by flow cytometry. Reduced or absent function of beta-c was demonstrated by ligand binding studies and progenitor clonogenic assays. Although molecular analysis of 1 patient identified what the authors referred to as a pro602-to-thr (P602T) mutation, this change was shown by Freeburn et al. (1996) to be a polymorphism (P603T with revised sequence).
In a Japanese woman with adult-onset pulmonary surfactant metabolism dysfunction-5 (SMDP5; 614370) manifest as pulmonary alveolar proteinosis, Tanaka et al. (2011) identified a homozygous truncating mutation in the CSF2RB gene (138981.0001). The heterozygous parents were heterozygous for the mutation. Tanaka et al. (2011) speculated that the late onset in this patient may have been due to compensatory factors such as increased serum GMCSF acting through an intact CSF2RA subunit (306250) or increased levels of other inflammatory cells.
In a girl with onset of pulmonary alveolar proteinosis at age 9 years, Suzuki et al. (2011) identified a homozygous missense mutation in the CSF2RB gene (S271L; 138981.0002). In vitro functional expression studies showed that the mutation resulted in a partial loss of function of GMCSF receptors.
Robb et al. (1995) used gene targeting to create mice with a null mutation of the common beta subunit of the Csf2rb1 gene (AIC2B). In the homozygous mice, high-affinity binding of GMCSF (138960) was abolished, while cells from heterozygous animals showed an intermediate number of high-affinity receptors. Binding of IL3 (147740) was unaffected, confirming that the IL3-specific beta-chain remained intact. Homozygous animals showed reduced eosinophil numbers in peripheral blood and bone marrow, while other hematologic parameters were normal. In clonal cultures of homozygous null bone marrow cells, even high concentrations of GMCSF and IL5 failed to stimulate colony formation, but the cells exhibited normal quantitative responsiveness to stimulation by IL3 and other growth factors. The mice exhibited normal development and survived to young adult life, although they developed pulmonary peribronchovascular lymphoid infiltrates and areas resembling alveolar proteinosis. There was no detectable difference in the systemic clearance and distribution of GMCSF.
D'Andrea et al. (1998) produced transgenic mice expressing a spontaneous mutation in the murine Csf2rb1 gene that confers growth factor-independent proliferation on primary committed myeloid progenitors. All transgenic mice displayed a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembled the human disease polycythemia vera (263300), suggesting that activating mutations in the CSF2RB gene may play a role in the pathogenesis of that myeloproliferative disorder. In addition, the transgenic mice developed a sporadic, progressive neurologic disorder and displayed bilateral, symmetrical foci of necrosis in the white matter of the brainstem associated with an accumulation of macrophages. D'Andrea et al. (1998) concluded that chronic CSF2RB activation also has the potential to contribute to pathologic events in the central nervous system.
Using Csf2rb-null mice, which develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (HPAP/SMDP) in children with CSF2RA or CSF2RB mutations, Suzuki et al. (2014) showed that pulmonary macrophage transplantation (PMT) of either wildtype or Csf2rb gene-corrected macrophages without myeloablation was safe and well tolerated. One administration corrected lung disease and secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least 1 year, as did therapeutic effects. Suzuki et al. (2014) concluded that their findings identified mechanisms regulating alveolar macrophage population size in health and disease, indicated that GMCSF is required for phenotypic determination of alveolar macrophages, and supported translation of PMT as the first specific therapy for children with hereditary pulmonary alveolar proteinosis.
In a Japanese woman with adult-onset pulmonary surfactant metabolism dysfunction-5 (SMDP5; 614370), manifest as pulmonary alveolar proteinosis and respiratory insufficiency, Tanaka et al. (2011) identified a homozygous 1-bp deletion (631delC) in exon 6 of the CSF2RB gene, resulting in a frameshift and premature termination. Each unaffected parent was heterozygous for the mutation. GMCSF was very high in the patient's serum and bronchoalveolar lavage, but autoantibodies to GMCSF were not found. In vitro studies showed that the patient's monocytes failed to differentiate into macrophages after stimulation with GMCSF. There was also a lack of STAT5 (601511) phosphorylation in response to GMCSF or IL3 stimulation, suggesting defective signaling by the common beta-subunit of the GMCSF receptor (CSF2RB). Flow cytometry of patient monocytes showed lack of CSF2RB expression, and CSF2RB mRNA was not detected in patient cells. Tanaka et al. (2011) speculated that the late onset in this patient may have been due to compensatory factors, such as increased serum GMCSF acting through an intact CSF2RA subunit (306250) or increased levels of other inflammatory cells.
In a girl with pulmonary surfactant metabolism dysfunction-5 (SMDP5; 614370), manifest as pulmonary alveolar proteinosis, Suzuki et al. (2011) identified a homozygous c.812C-T transition in exon 7 of the CSF2RB gene, resulting in a ser271-to-leu (S271L) substitution. The unaffected parents were heterozygous for the mutation. In vitro functional expression studies in patient cells showed that the mutation impaired STAT5 phosphorylation following stimulation by GMCSF and IL3. In HEK293 cells transfected with the mutation, increased concentrations of GMCSF demonstrated partial functioning of the mutant receptor, suggesting that GMCSF therapy may be of clinical benefit.
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Jenkins, B. J., D'Andrea, R., Gonda, T. J. Activating point mutations in the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors suggest the involvement of beta subunit dimerization and cell type-specific molecules in signalling. EMBO J. 14: 4276-4287, 1995. [PubMed: 7556069] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb00102.x]
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Shen, Y., Baker, E., Callen, D. F., Sutherland, G. R., Willson, T. A., Rakar, S., Gough, N. M. Localization of the human GM-CSF receptor beta chain gene (CSF2RB) to chromosome 22q12.2-q13.1. Cytogenet. Cell Genet. 61: 175-177, 1992. [PubMed: 1424804] [Full Text: https://doi.org/10.1159/000133401]
Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., Trapnell, B. C. Pulmonary macrophage transplantation therapy. Nature 514: 450-454, 2014. [PubMed: 25274301] [Full Text: https://doi.org/10.1038/nature13807]
Suzuki, T., Maranda, B., Sakagami, T., Catellier, P., Couture, C.-Y., Carey, B. C., Chalk, C., Trapnell, B. C. Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations. (Letter) Europ. Resp. J. 37: 201-204, 2011. [PubMed: 21205713] [Full Text: https://doi.org/10.1183/09031936.00090610]
Tanaka, T., Motoi, N., Tsuchihashi, Y., Tazawa, R., Kaneko, C., Nei, T., Yamamoto, T., Hayashi, T., Tagawa, T., Nagayasu, T., Kuribayashi, F., Ariyoshi, K., Nakata, K., Morimoto, K. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB. J. Med. Genet. 48: 205-209, 2011. [PubMed: 21075760] [Full Text: https://doi.org/10.1136/jmg.2010.082586]
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