Alternative titles; symbols
HGNC Approved Gene Symbol: CSF3R
SNOMEDCT: 129639005;
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:36,466,043-36,483,314 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.3 | ?Neutrophilia, hereditary | 162830 | Autosomal dominant | 3 |
| Neutropenia, severe congenital, 7, autosomal recessive | 617014 | Autosomal recessive | 3 |
The CSF3R gene encodes the receptor for granulocyte colony-stimulating factor (CSF3; 138970), a 20- to 25-kD glycoprotein produced by macrophages stimulated with endotoxin, that plays an important role in granulopoiesis during the inflammatory process (summary by Fukunaga et al., 1990).
Fukunaga et al. (1990) cloned and characterized cDNAs for human CSF3 receptor. They found that it is abundantly expressed in the human placenta. The receptor contains 813 amino acids and shows marked homology (62.5%) with its murine counterpart. It was found to consist of extracellular, transmembrane, and cytoplasmic domains. Two other classes of the human CSF3 receptor were identified, one of which had a deletion of the transmembrane domain and seemed to represent a secreted, soluble receptor. The third class contained a 27-amino acid insertion in the cytoplasmic domain and was highly expressed in the placenta. Binding studies with radiolabeled CSF3 indicated that CSF3 receptor is expressed not only by progenitor and mature neutrophilic granulocytes, but also by nonhematopoietic cells such as placental cells, endothelial cells, and various carcinoma cell lines.
Seto et al. (1992) found that CSF3R is subdivided into several regions: an Ig-like domain, a cytokine receptor homologous domain, 3 fibronectin type III domains, a transmembrane domain, and a cytoplasmic region. No canonical 'TATA' box was found upstream of the cap site. About 110 bp upstream of the transcription initiation site, an 18-bp element was found that is homologous to sequences found in the promoter of human myeloperoxidase (606989) and neutrophil elastase (130120) genes.
Dong et al. (2001) reported that the C terminus of CSF3R is required for SHP1 (176883) downregulation of CSF3-induced STAT activation. The authors proposed that this mechanism inhibits cell proliferation and survival in response to CSF3.
Seto et al. (1992) determined that the CSF3R gene contains 17 exons.
By in situ hybridization using human CSF3R cDNA as a probe, Inazawa et al. (1991) localized the gene to 1p35-p34.3. The localization on chromosome 1 was confirmed by 2 further methods: the use of oligonucleotides specific for human CSF3R for PCR amplification of DNA from mouse A9 cells that contained chromosome 1 as the only human chromosome; and spot-blot hybridization of sorted human chromosomes.
Tweardy et al. (1992) assigned the gene to the distal short arm of human chromosome 1 by Southern blot analysis of its segregation pattern in a panel of rodent-human hybrid DNAs. By chromosomal in situ hybridization, they refined the localization to 1p34-p32 and concluded that the gene is located telomeric to the CSF1 (120420), JUN (165160), and TCL5 (187040) genes.
Hereditary Neutrophilia
In a 3-generation family segregating autosomal dominant neutrophilia (162830), Plo et al. (2009) sequenced the CSF3R gene and identified a heterozygous mutation (T617N; 138971.0001) in all 12 affected individuals that was not found in the 4 unaffected family members. The T617N mutation had previously been reported as an acquired activating mutation in 2 of 555 patients with acute myeloid leukemia by Forbes et al. (2002). In these 2 cases, the mutation was acquired because it disappeared after complete remission achievement and was not detected at relapse.
Severe Congenital Neutropenia 7, Autosomal Recessive
In affected children from 2 unrelated families with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014), Triot et al. (2014) identified biallelic mutations in the CSF3R gene (138971.0002-138971.0004). The mutation in the first family was a homozygous missense mutation (R308C; 138971.0002), which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. Transfection studies in bone marrow cells showed that the R308C mutant protein was retained in the endoplasmic reticulum and not expressed on the plasma membrane. Cells expressing the mutant receptor had decreased downstream signaling compared to wildtype, but signal transduction was not completely abrogated. The patient in the second family was compound heterozygous for 2 truncating mutations (138971.0003-138971.0004), consistent with a loss of function.
In a female infant with SCN7, Klimiankou et al. (2015) identified compound heterozygous truncating mutations in the CSF3R gene (138971.0005-138971.0006). The mutations, which were found by direct sequencing of the CSF3R gene, segregated with the disorder in the family. No expression of CSF3R was detected on patient neutrophils or monocytes.
Somatic Mutations
Dong et al. (1994) identified a somatic point mutation in the GCSFR gene as the cause of acute myeloid leukemia (AML) in a patient with severe congenital neutropenia (202700). Dong et al. (1995) described somatic mutations in the GCSFR gene in 2 males with acute myeloid leukemia preceded by severe congenital neutropenia. In 1 patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. Transfection of the cDNA encoding the mutant GCSF receptor into mouse cells resulted in abnormally high proliferative responses but failure to mature when cultured in GCSF. The mutant receptors also interfered with terminal maturation mediated by the wildtype GCSF receptor and the murine cells that coexpressed the wildtype and mutant receptors, an apparent dominant-negative effect.
Tidow et al. (1997) investigated the frequency of these specific mutations in patients with congenital neutropenia undergoing treatment with recombinant human granulocyte colony-stimulating factor (Filgrastim). The critical region (nucleotides 2384-2429) from the intracellular domain of the GCSFR gene was studied in both genomic DNA and cDNA from neutrophils and mononuclear cells from 28 patients with severe congenital neutropenia. In 4 of the patients, a point mutation in the tested cytoplasmic region of the GCSFR gene was found. The point mutations replaced a glutamine codon by a stop codon. Among these 4 congenital neutropenia patients with a mutated GCSFR gene, 2 developed AML. All 4 patients were investigated regularly and no correlation between occurrence of GCSFR mutation and time or dose of Filgrastim was found. No point mutations in the GCSFR critical domain could be detected in cells from the other 24 congenital neutropenia patients. Furthermore, Tidow et al. (1997) tested 6 family members of the 2 patients with AML, including mothers and fathers, 1 sister, and 1 brother who also suffered from congenital neutropenia. All family members had a normal GCSFR gene. After the acquisition of the GCSFR mutations, the congenital neutropenia patients continued to respond to G-CSFR therapy with an increase in absolute neutrophils in the peripheral blood. Tidow et al. (1997) concluded that the point mutations in the critical region of the intracellular part of the G-CSF receptor occur spontaneously and are not inherited. They suggested, furthermore, that the described point mutations do not alter the response to treatment and are not the cause of severe congenital neutropenia.
Dale et al. (2000) quoted prevalence data suggesting that a minority of patients with congenital neutropenia show mutations in GCSFR. On the other hand, mutations in the neutrophil elastase gene (ELA2; 130130) have been identified in a majority of these patients. Dale et al. (2000) suggested that it is much more likely that mutations in the ELA2 gene compromise myeloid differentiation and create a risk for development of acute myeloid leukemia.
Maxson et al. (2013) identified activating mutations in the CSF3R gene in 16 of 27 patients (59%) with chronic neutrophilic leukemia (CNL) or atypical (BCR-ABL1-negative; see 608232) chronic myeloid leukemia (CML). These mutations segregated within 2 distinct regions of CSF3R and led to preferential downstream kinase signaling through SRC family (see 190090)-TNK2 (606994) or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 (see 147795) inhibitor ruxolitinib.
Klimiankou et al. (2016) noted that more than 80% of patients with severe congenital neutropenia, regardless of genetic origin, who develop AML or myelodysplastic syndrome have somatic mutations in the intracellular part of the CSF3R gene, resulting in changes in the downstream signaling pathways. Acquisition of these somatic mutations is an SCN-specific phenomenon and is associated with inherited mutations causing SCN or cyclic neutropenia (162800), such as those in the ELANE (130130) or HAX1 (605998) genes. The majority of cytoplasmic CSF3R mutations occur between Y727 and Y752 (NP_000751.3, numbering including the signal peptide sequence). In addition, CSF3R mutant clones are highly dynamic and may disappear and reappear during continuous treatment with G-CSF, and the time between detection of somatic CSF3R mutations and onset of leukemia can range from months to years.
Despite the demonstration of mutations in CSF3R, their role in the pathogenesis of SCN and the subsequent development of acute myeloid leukemia remained controversial. McLemore et al. (1998) generated mice carrying a targeted mutation in their Csf3r gene that reproduced a mutation found in a patient with SCN and AML reported by Dong et al. (1995). They found that the mutant Csf3r allele was expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation had normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis was normal. However, in response to GCSF treatment, these mice demonstrated a significantly greater increase in the level of circulating neutrophils. This effect appeared to be due to increased neutrophil production. Furthermore, the in vitro survival and GCSF-dependent suppression of apoptosis of mutant neutrophils were normal. Despite this evidence for a hyperproliferative response to GCSF, no cases of AML were detected. McLemore et al. (1998) interpreted the results as providing strong evidence that mutations in the CSF3R gene are not responsible for the impaired granulopoiesis present in patients with SCN.
Schweizerhof et al. (2009) presented evidence that GCSF and GMCSF (CSF2; 138960) 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 and GMCSFR (CSF2RA; 306250) 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 mouse sarcoma model led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain.
In 12 affected members of a 3-generation family segregating autosomal dominant hereditary neutrophilia (162830), Plo et al. (2009) identified heterozygosity for a 2088C-A transversion in the CSF3R gene, resulting in a thr617-to-asn (T617N) substitution located in the transmembrane domain of the receptor. Computational analysis by Plo et al. (2009) indicated that T617N strongly favors dimerization of the receptor transmembrane domain, and studies in CD34+ cells from patients and controls demonstrated constitutive activation of the mutant receptor with hypersensitivity to GCSF. Mutant hematopoietic stem cells yielded a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The T617N mutation had previously been reported as an acquired activating mutation in 2 of 555 patients with acute myeloid leukemia by Forbes et al. (2002).
In 2 sibs, born of consanguineous Turkish parents, with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014), Triot et al. (2014) identified a homozygous c.922C-T transition (c.922C-T, NM_000760.3) in the CSF3R gene, resulting in an arg308-to-cys (R308C) substitution at a highly conserved residue next to the WSXWS motif. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Transfection of the mutation into HeLa cells showed that the mutant protein had a decreased molecular weight compared to wildtype, resulting from different N-glycosylation patterns. Additional expression studies in bone marrow cells showed that the mutant protein was retained in the endoplasmic reticulum and not expressed on the plasma membrane. Cells expressing the mutant receptor had decreased downstream signaling compared to wildtype, but signal transduction was not completely abrogated. One of the sibs, who also had dextrocardia and symptoms of a primary ciliary dyskinesia, also had a homozygous truncating mutation in the SPAG1 gene (603395), resulting in CILD28 (615505).
Im a 9-month-old girl, born of unrelated Spanish parents, with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014), Triot et al. (2014) identified compound heterozygous truncating mutations in the CSF3R gene: a 16-bp deletion (c.948_963del, NM_000760.3) in exon 8, resulting in a frameshift and premature termination (Gly316fsTer322), and a 1-bp deletion (c.1245del; 138971.0004) in exon 10, resulting in a frameshift and premature termination (Gly415fsTer432). The mutations segregated with the disorder in the family. Patient peripheral blood cells showed markedly decreased surface expression of CSF3R compared to controls, consistent with a loss of function.
For discussion of the 1-bp deletion (c.1245del, NM_000760.3) in exon 10 of the CSF3R gene, resulting in a frameshift and premature termination (Gly415fsTer432), that was found in a patient with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014) by Triot et al. (2014), see 138971.0003.
In a female infant with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014), Klimiankou et al. (2015) identified compound heterozygous truncating mutations in the CSF3R gene: an A-to-T transversion in intron 8 (c.998-2A-T), resulting in the skipping of exon 9 and a shift in the reading frame, and a mutation resulting in a trp547-to-ter (W547X; 138971.0006) substitution. The mutations, which were found by direct sequencing of the CSF3R gene, segregated with the disorder in the family. No expression of CSF3R was detected on patient neutrophils or monocytes. The patient did not respond to G-CSF treatment, but did respond to GM-CSF treatment.
For discussion of the trp547-to-ter (W547X; 138971.0006) substitution in the CSF3R gene that was found in compound heterozygous state in a patient with autosomal recessive severe congenital neutropenia-7 (SCN7; 617014) by Klimiankou et al. (2015), see 138971.0005.
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