Alternative titles; symbols
HGNC Approved Gene Symbol: CSF2RA
Cytogenetic location: Xp22.33 Genomic coordinates (GRCh38): X:1,268,814-1,325,218 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.33 | Surfactant metabolism dysfunction, pulmonary, 4 | 300770 | 3 |
Granulocyte/macrophage colony-stimulating factor (GMCSF, or CSF2; 138960) activates STAT5 (601511) and other signaling pathways via binding to a cell surface receptor composed of a ligand-binding alpha subunit, encoded by CSF2RA, and a nonbinding affinity-enhancing beta subunit, encoded by CSF2RB (138981) (Suzuki et al., 2008).
Using an expression cloning strategy, Gearing et al. (1989) isolated a cDNA encoding CSF2RA, which they called GMCSFR, from a human placenta cDNA library. The deduced 400-amino acid precursor protein has a 22-amino acid signal peptide. The 378-amino acid mature protein has a calculated molecular mass of 43.7 kD and contains a single transmembrane domain, a glycosylated extracellular domain, and a short intracytoplasmic tail. Northern blot analysis detected GMCSFR expression in a variety of hemopoietic cells displaying GMCSF binding.
Raines et al. (1991) identified a truncated, soluble form of the low-affinity GMCSF receptor in choriocarcinoma cells. Clones encoding the soluble receptor were identical in sequence to the membrane-bound form except for a 97-nucleotide deletion. The amino acid sequence of this deleted cDNA predicted a protein that lacks the 84 C-terminal amino acids of the membrane-bound receptor, including the transmembrane and cytoplasmic domains, and contains 16 different amino acids at its C terminus. RNase protection analysis indicated that this variant cDNA was derived from a naturally occurring mRNA. Soluble receptors had been identified for several other hematopoietin receptors and may be a general feature of this class. It is likely that alternative mRNA splicing is the mechanism by which the soluble counterparts are generated.
Rappold et al. (1992) found that the CSF2RA gene spans at least 45 kb.
By Southern blot analysis of a panel of mouse-human somatic cell hybrids, Gough et al. (1990) demonstrated that the CSF2R gene is on the X chromosome. The possibility that an allele also maps to the Y chromosome was suggested by the observation that many DNA samples from normal males carry 2 alleles of this gene. Among 65 normal persons, 23 females and 20 males were homozygous for an allele of fragment A, whereas 8 females and 14 males were heterozygous. By in situ hybridization, Gough et al. (1990) showed that the CSF2R gene maps to the tip of the short arm of the X chromosome and the short arm of the Y chromosome (see 425000), with the most likely localization being Xpter-p21 and Ypter-p11.2. Although this information was consistent with its location in the pseudoautosomal region (PAR), conclusive proof required study of segregation of the locus with respect to sexual phenotype. They found in a total of 14 informative male meioses, 3 recombination events; i.e., in 2 cases a daughter had inherited the allele from the paternal Y chromosome, and in 1 instance a son had inherited the allele from the paternal X chromosome. Thus, the CSF2R locus is distal to the MIC2 locus (313470), which shows only about 2.5% recombination and maps close to the PAR boundary. This was the first localization of a gene of known function to this region, which encompasses about 2,500 kb.
By pulsed field gel electrophoresis, Rappold et al. (1992) localized the CSF2RA gene 1,180 to 1,300 kb from the telomere, in close proximity to the CpG island B5. The gene showed abundant hypervariable sequences, and a number of informative restriction fragment length polymorphisms were defined. Rappold et al. (1992) suggested that these polymorphisms might be useful in proving the pseudoautosomal inheritance of apparently autosomal traits, as has been suggested for schizophrenia (Crow, 1988), cerebral dominance (Crow, 1989), and Kabuki make-up syndrome (Niikawa et al., 1988; 147920), among others.
Rappold (1993) discussed in detail the pseudoautosomal regions that exist at the tips of the short and long arms of the X and Y chromosomes and cover 2.6 and 0.4 Mb, respectively.
By both in situ hybridization and linkage analysis, Disteche et al. (1992) found that the murine Csf2ra gene maps to chromosome 19.
DiPersio et al. (1988) studied the binding of GMCSF, over a wide range of concentrations, to normal human peripheral blood cells, bone marrow, acute and chronic myeloid leukemia cells, and a number of established human myeloid and nonmyeloid cell lines; thereby, they defined the receptors.
Gearing et al. (1989) found that transfection of GMCSFR cDNA into COS cells directed expression of a GMCSF receptor showing a single class of affinity and specificity for human GMCSF, but not interleukin-3 (IL3; 147740).
Hayashida et al. (1990) showed that the high-affinity GMCSF receptor is composed of at least 2 components in a manner analogous to the IL2 receptor (see 147730). They proposed to designate the low-affinity GMCSF receptor as the alpha subunit, and the 'new' protein that they identified and called KH97 as the beta subunit (see 138981). The 2 subunits are approximately 80 and 120 kD, respectively.
Raines et al. (1991) found that expression of the variant cDNA encoding the truncated, soluble CSF2R isoform produced a secreted protein that retained its capacity to bind CSF2 in solution.
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.
Loss of either the X or the Y chromosome is apparent in 25% of acute myeloid leukemias of the M2 subtype (AML-M2), compared with only 1 to 6% in other AML subtypes, suggesting the involvement of a 'recessive oncogene' in the genesis of M2 AMLs. The presumed gene is likely to be in the PAR, because if it were located in the portion of the X chromosome not shared with the Y, then similar loss of the Y chromosome would not be predicted, and vice versa. Gough et al. (1990) suggested that CSF2R may be the gene in question. Loss or inactivation of both copies of the gene in a myeloid progenitor cell would be expected to result in a clone of cells unable to respond to GMCSF, and hence in the relatively undifferentiated phenotype of the M2 form of leukemia.
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. It is a disorder of surfactant metabolism. The importance of CSF2 in the pathogenesis of PAP has been confirmed in humans and mice, wherein CSF2 signaling is required for pulmonary alveolar macrophage catabolism of surfactant. Using flow cytometry, Martinez-Moczygemba et al. (2008) found that CSF2RA was absent on monocytes from a 4-year-old girl with PAP due to pulmonary surfactant metabolism dysfunction (SMDP4; 300770). The patient's mother expressed CSF2RA on all monocytes, whereas the patient's father and sister expressed CSF2RA only on a subpopulation of monocytes. Stimulation of granulocytes with CSF2 induced upregulation of CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic analysis showed that the patient had 1 X chromosome of apparently normal length and 1 X chromosome with a truncated Xp arm that did not hybridize with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA in leukocytes from the patient's family members, but not in those from the patient. PCR analysis of the 11 coding exons of the CSF2RA gene revealed a deletion of exons 5 through 13 (306250.0001) in the patient's DNA, providing a genetic basis for the absence of CSF2RA mRNA and protein.
Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and CSF2RB were present on leukocytes from 2 sisters with PAP, as well as all family members tested. However, Western blot analysis showed that the affected sisters expressed only a truncated form of CSF2RA, whereas their father was heterozygous for the normal and truncated forms, and their mother expressed only normal CSF2RA. CSF2 binding and CSF2-dependent signaling were severely reduced, but not abolished, in the sisters, and their CD11B stimulation test was abnormal. Suzuki et al. (2008) identified a mutation in the CSF2RA gene in the affected sisters that resulted in a gly174-to-arg (G174R; 306250.0002) substitution. The father was heterozygous for the G174R mutation, but the mother had only wildtype CSF2RA. PCR analysis showed that CSF2RA copy number was reduced in the sisters and their mother, but not in the father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1 X chromosome of the sisters and mother. Suzuki et al. (2008) concluded that PAP may be caused by compound heterozygous abnormalities affecting the CSF2RA gene, and that CSF2 signaling is critical for surfactant homeostasis in humans.
Schweizerhof et al. (2009) presented evidence that GCSF (CSF3; 138970) and GMCSF mediate bone cancer pain and tumor-nerve interactions. Increased levels of both factors were detected in bone marrow lysates and adjoining connective tissue in a mouse sarcoma model of bone tumor-induced pain compared to controls. The functional receptors GCSFR (CSF3R; 138971) and GMCSFR were expressed on peripheral nerves in the bone matrix and in dorsal root ganglia. GMCSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP (114130) release, and caused sprouting of sensory nerve endings in the skin. RNA interference of GCSF and GMCSF signaling in the mouse sarcoma model led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain.
In a 4-year-old girl with pulmonary alveolar proteinosis (SMDP4; 300770), Martinez-Moczygemba et al. (2008) identified a deletion of exons 5 through 13 in the CSF2RA gene. Karyotypic analysis showed that the patient's other X chromosome had a truncated Xp arm that did not hybridize with a probe for pseudoautosomal region-1, which contains CSF2RA. The patient's mother expressed CSF2RA on all monocytes, whereas the patient's father and sister expressed CSF2RA only on a subpopulation of monocytes. Stimulation of granulocytes with CSF2 (138960) induced upregulation of CD11B (ITGAM; 120980) in the mother, but not the patient. RT-PCR analysis detected expression of CSF2RA in leukocytes from the patient's family members, but not in those from the patient.
Suzuki et al. (2008) identified a G-to-A transition in exon 7 of the CSF2RA gene in genomic DNA from 2 sisters with pulmonary alveolar proteinosis (SMDP4; 300770), one 6 years of age and the other 8 years of age. The mutation resulted in a gly174-to-arg (G174R) substitution that altered 1 of 11 potential N-glycosylation sites in the CSF2RA protein. Western blot analysis showed that the affected sisters expressed only a truncated form of CSF2RA, whereas their father was heterozygous for the normal and truncated forms, and their mother expressed only normal CSF2RA. CSF2 (138960) binding and CSF2-dependent signaling were severely reduced, but not abolished, in the sisters, and their CD11B (120980) stimulation test was abnormal. The father was heterozygous for the G174R mutation, but the mother had only wildtype CSF2RA. PCR analysis showed that CSF2RA copy number was reduced in the sisters and their mother, but not in the father. FISH analysis demonstrated a 1.6-Mb deletion of pseudoautosomal region-1, including the CSF2RA gene, in 1 X chromosome of the sisters and mother. Transfection of CSF2RA with the G174R mutation into 293 cells reproduced the CSF2 signaling defect at physiologic CSF2 concentrations. At high CSF2 concentrations, similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow disease progression in the 2 sisters.
Crow, T. J. Sex chromosomes and psychosis: the case for a pseudoautosomal locus. Brit. J. Psychiat. 153: 675-683, 1988. [PubMed: 3255457] [Full Text: https://doi.org/10.1192/bjp.153.5.675]
Crow, T. J. Pseudoautosomal locus for the cerebral dominance gene. (Letter) Lancet 334: 339-340, 1989. Note: Originally Volume II. [PubMed: 2569145] [Full Text: https://doi.org/10.1016/s0140-6736(89)90530-8]
DiPersio, J., Billing, P., Kaufman, S., Eghtesady, P., Williams, R. E., Gasson, J. C. Characterization of the human granulocyte-macrophage colony-stimulating factor receptor. J. Biol. Chem. 263: 1834-1841, 1988. [PubMed: 2828352]
Disteche, C. M., Brannan, C. I., Larsen, A., Adler, D. A., Schorderet, D. F., Gearing, D., Copeland, N. G., Jenkins, N. A., Park, L. S. The human pseudoautosomal GM-CSF receptor alpha subunit gene is autosomal in mouse. Nature Genet. 1: 333-336, 1992. [PubMed: 1363815] [Full Text: https://doi.org/10.1038/ng0892-333]
Gearing, D. P., King, J. A., Gough, N. M., Nicola, N. A. Expression cloning of a receptor for granulocyte-macrophage colony-stimulating factor. EMBO J. 8: 3667-3676, 1989. [PubMed: 2555171] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08541.x]
Gough, N. M., Gearing, D. P., Nicola, N. A., Baker, E., Pritchard, M., Callen, D. F., Sutherland, G. R. Localization of the human GM-CSF receptor gene to the X-Y pseudoautosomal region. Nature 345: 734-736, 1990. [PubMed: 1972780] [Full Text: https://doi.org/10.1038/345734a0]
Hayashida, K., Kitamura, T., Gorman, D. M., Arai, K., Yokota, T., Miyajima, A. Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor. Proc. Nat. Acad. Sci. 87: 9655-9659, 1990. [PubMed: 1702217] [Full Text: https://doi.org/10.1073/pnas.87.24.9655]
Kondo, M., Scherer, D. C., Miyamoto, T., King, A. G., Akashi, K., Sugamura, K., Weissman, I. L. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 407: 383-386, 2000. [PubMed: 11014194] [Full Text: https://doi.org/10.1038/35030112]
Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1. J. Exp. Med. 205: 2711-2716, 2008. [PubMed: 18955567] [Full Text: https://doi.org/10.1084/jem.20080759]
Niikawa, N., Kuroki, Y., Kajii, T., Matsuura, N., Ishikiriyama, S., Tonoki, H., Ishikawa, N., Yamada, Y., Fujita, M., Umemoto, H., Iwama, Y., Kondoh, I., and 34 others. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am. J. Med. Genet. 31: 565-589, 1988. [PubMed: 3067577] [Full Text: https://doi.org/10.1002/ajmg.1320310312]
Raines, M. A., Liu, L., Quan, S. G., Joe, V., DiPersio, J. F., Golde, D. W. Identification and molecular cloning of a soluble human granulocyte-macrophage colony-stimulating factor receptor. Proc. Nat. Acad. Sci. 88: 8203-8207, 1991. [PubMed: 1832774] [Full Text: https://doi.org/10.1073/pnas.88.18.8203]
Rappold, G. A. The pseudoautosomal regions of the human sex chromosomes. Hum. Genet. 92: 315-324, 1993. [PubMed: 8225310] [Full Text: https://doi.org/10.1007/BF01247327]
Rappold, G., Willson, T. A., Henke, A., Gough, N. M. Arrangement and localization of the human GM-CSF receptor alpha chain gene CSF2RA within the X-Y pseudoautosomal region. Genomics 14: 455-461, 1992. [PubMed: 1358805] [Full Text: https://doi.org/10.1016/s0888-7543(05)80241-1]
Schweizerhof, M., Stosser, S., Kurejova, M., Njoo, C., Gangadharan, V., Agarwal, N., Schmelz, M., Bali, K. K., Michalski, C. W., Brugger, S., Dickenson, A., Simone, D. A., Kuner, R. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. (Letter) Nature Med. 15: 802-807, 2009. [PubMed: 19525966] [Full Text: https://doi.org/10.1038/nm.1976]
Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J. Exp. Med. 205: 2703-2710, 2008. [PubMed: 18955570] [Full Text: https://doi.org/10.1084/jem.20080990]