Alternative titles; symbols
HGNC Approved Gene Symbol: FGR
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:27,612,064-27,635,185 (from NCBI)
The cell-derived domain of Gardner-Rasheed feline sarcoma virus consists of a gamma-actin sequence and a tyrosine-specific protein kinase sequence called v-fgr. By means of a v-fgr probe, Tronick et al. (1985) isolated a human homolog. Analysis showed that the human DNA is distinct from all other retroviral oncogenes.
Tronick et al. (1985) localized the FGR oncogene to 1p36.2-p36.1 by in situ hybridization. By Southern analysis of somatic cell hybrids, Nishizawa et al. (1986) confirmed the assignment of the FGR locus to chromosome 1.
FGR is the same as the oncogene earlier called SRC2. The latter was mapped to 1p36-p34 by Le Beau et al. (1984) using in situ hybridization and by Lebo et al. (1984) using dual-beam chromosome sorting and spot blot DNA analysis. Dracopoli et al. (1988) assigned SRC2 to 1p by analysis of DNA from a panel of somatic cell hybrids and by linkage analysis in the CEPH families. The latter studies showed that the SRC2 locus is 3.1 cM from the Rh blood group locus (see 111700). They favored the gene order: 1pter--PND--ALPL--FUCA1--SRC2(FGR)--Rh--D1S57--MYCL.
Stumpf (2020) mapped the FGR gene to chromosome 1p35.3 based on an alignment of the FGR sequence (GenBank BC064382) with the genomic sequence (GRCh38).
For discussion of a possible association between variation in the FGR gene and chronic recurrent multifocal osteomyelitis (CRMO; 259680), see 164940.0001 and 164940.0002.
Abe et al. (2019) studied Ali18 mice, which were isolated from a mutagenesis screen and exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. Using positional cloning with a candidate-gene approach, they identified a D502G substitution at a conserved residue within the C-terminal end of the catalytic domain of the Fgr gene. Introduction of N-terminal deletions using CRISPR/Cas9 abolished the inflammatory phenotype in Ali19 mice, and Fgr null mutant mice were morphologically normal, but mice with in-frame and missense mutations in the same region continued to exhibit the phenotype. Kinase assay experiments demonstrated reduced C-terminal phosphorylation of the mutant protein compared to wildtype Fgr, suggesting that D502G is a gain-of-function mutation.
This variant is classified as a variant of unknown significance because its contribution to chronic recurrent multifocal osteomyelitis (CRMO; 259680) has not been confirmed.
By exome sequencing in a cohort of 99 probands with chronic recurrent multifocal osteomyelitis (CRMO; 259680), Abe et al. (2019) identified a child (case 1), negative for mutation in known CRMO susceptibility genes, who was heterozygous for a G-to-A transition (chr1.27,948,146G-A, GRCh37) in the FGR gene, resulting in an arg118-to-trp (R118W) substitution in a beta strand near the distal loop of the SH3 domain. The mutation, which was shown to have arisen de novo in the proband, was present in the gnomAD database at a minor allele frequency of 1.2 x 10(-5). Kinase assay experiments showed significantly decreased phosphorylation with the mutant compared to wildtype FGR. Because the mutant construct showed decreased kinase activity, the authors stated that the role of the R118W mutation in CRMO pathogenesis was difficult to define and that further studies would be needed. Patient radiographs showed osteolytic lesions with sclerosis and periosteal elevation of the right distal femur. MRI showed increased STIR signal intensity on the iliac and sacral sides of the left sacroiliac joint.
This variant is classified as a variant of unknown significance because its contribution to chronic recurrent multifocal osteomyelitis (CRMO; 259680) has not been confirmed.
By exome sequencing in a cohort of 99 probands with chronic recurrent multifocal osteomyelitis (CRMO; 259680), Abe et al. (2019) identified a child (case 2), negative for mutation in known CRMO susceptibility genes, who was heterozygous for a G-to-A transition (chr1.27,939,442G-A, GRCh37) in the FGR gene, resulting in a pro525-to-ser (P525S) substitution at a conserved residue within the C-terminal tail that interacts with the SH2 domain. The mutation, which was not present in the 1 parent from whom DNA was available, was present in the gnomAD database at a minor allele frequency of 3.5 x 10(-4). Kinase assay experiments showed significantly increased phosphorylation with the mutant compared to wildtype FGR. Patient MRI showed increased signal intensity on STIR images in the left distal fibula and the pelvis at the right acetabulum. Repeat MRI 9 months after nonsteroidal antiinflammatory treatment showed improvement in the left acetabular lesion.
Abe, K., Cox, A., Takamatsu, N., Velez, G., Laxer, R. M., Tse, S. M. L., Mahajan, V. B., Bassuk, A. G., Fuchs, H., Ferguson, P. J., Hrabe de Angelis, M. Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans. Proc. Nat. Acad. Sci. 116: 11872-11877, 2019. [PubMed: 31138708] [Full Text: https://doi.org/10.1073/pnas.1819825116]
Cheah, M. S. C., Ley, T. J., Tronick, S. R., Robbins, K. C. Fgr proto-oncogene mRNA induced in B lymphocytes by Epstein-Barr virus infection. Nature 319: 238-240, 1986. [PubMed: 3003578] [Full Text: https://doi.org/10.1038/319238a0]
Dracopoli, N. C., Stanger, B. Z., Lager, M., Housman, D. E. Localization of the FGR protooncogene on the genetic linkage map of human chromosome 1p. Genomics 3: 124-128, 1988. [PubMed: 2906322] [Full Text: https://doi.org/10.1016/0888-7543(88)90142-5]
Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D. Evidence for two distinct c-src loci on human chromosomes 1 and 20. Nature 312: 70-71, 1984. [PubMed: 6092965] [Full Text: https://doi.org/10.1038/312070a0]
Lebo, R. V., Cheung, M.-C., Bruce, B. D. Rapid gene mapping by dual laser chromosome sorting and spot blot DNA analysis. (Abstract) Am. J. Hum. Genet. 36: 101S, 1984.
Nishizawa, M., Semba, K., Yoshida, M. C., Yamamoto, T., Sasaki, M., Toyoshima, K. Structure, expression, and chromosomal location of the human c-fgr gene. Molec. Cell. Biol. 6: 511-517, 1986. [PubMed: 3023853] [Full Text: https://doi.org/10.1128/mcb.6.2.511-517.1986]
Parker, R. C., Mardon, G., Lebo, R. V., Varmus, H. E., Bishop, J. M. Isolation of duplicated human c-src genes located on chromosomes 1 and 20. Molec. Cell. Biol. 5: 831-838, 1985. [PubMed: 2581127] [Full Text: https://doi.org/10.1128/mcb.5.4.831-838.1985]
Stumpf, A. M. Personal Communication. Baltimore, Md. 11/04/2020.
Tronick, S. R., Popescu, N. C., Cheah, M. S. C., Swan, D. C., Amsbaugh, S. C., Lengel, C. R., DiPaolo, J. A., Robbins, K. C. Isolation and chromosomal localization of the human fgr protooncogene, a distinct member of the tyrosine kinase gene family. Proc. Nat. Acad. Sci. 82: 6595-6599, 1985. [PubMed: 2995972] [Full Text: https://doi.org/10.1073/pnas.82.19.6595]