Alternative titles; symbols
HGNC Approved Gene Symbol: FCGRT
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,512,661-49,526,428 (from NCBI)
The intestinal epithelium of neonatal mice and rats expresses an Fc receptor (FcRn) that mediates the selective uptake of immunoglobulin G (IgG) in mothers' milk, thereby helping newborn animals to acquire passive immunity. Kandil et al. (1996) noted that the IgG in the milk is bound to FcRn at the apical surface of the intestinal epithelium, and the resultant FcRn-IgG complexes are transcytosed across the epithelium. At the basolateral surface of intestinal epithelial cells, IgG is released from FcRn into blood or tissue fluids. FcRn is structurally similar to the major histocompatibility complex class I molecule, which presents antigenic peptides to T cells. Like the MHC class I molecule, FcRn is made up of a heavy chain (approximately 48 kD) and beta-2-microglobulin (109700; approximately 12 kD). Its heavy chain shows approximately 35% amino acid sequence identity to that of a typical MHC class I molecule. Furthermore, the genomic organizations of the MHC class I and mouse FcRn heavy chain genes are similar in that the signal peptide, the 3 extracellular domains, the transmembrane region, and the cytoplasmic region are all encoded by separate exons. Story et al. (1994) cloned a cDNA encoding the human gene and symbolized it FcRn. Kandil et al. (1996) isolated human genomic clones for the gene (symbolized FCGRT by them) using 2 murine Fcgrt probes. The exonic sequences of the genomic clones are identical to the cDNA sequence described by Story et al. (1994).
Plasma protein catabolism occurs in vascular endothelium by endocytotic processing of plasma contents. Vascular endothelium is the most active endocytic tissue in the body and the principal site for plasma protein catabolism. Plasma proteins diffusing or transported into extravascular sites are isolated from catabolism while extravascular. The receptor encoded by the FCGRT gene, alternatively called the Brambell receptor, the protection receptor, or the neonatal receptor, is located in endosomes of vascular endothelial cells and selectively recycles IgG to the cell surface, thus protecting IgG from lysosomal catabolism that is the fate of other, nonprotected plasma proteins. In mice with knockout of this receptor, the fractional catabolic rate for IgG may be accelerated up to 10-fold relative to wildtype animals in which protection is intact (Junghans and Anderson, 1996). This protection mechanism is directly responsible for making IgG the longest lived of all plasma proteins (Waldmann and Strober, 1969).
Junghans et al. (2001) postulated that long-range cis inactivation of the FCGRT gene is responsible for hypercatabolism of IgG in myotonic dystrophy (DM; 160900). The FCGRT gene is closely situated to the DMPK gene (605377), which is mutant in DM.
Ahouse et al. (1993) found that the mouse FcRn heavy chain gene, designated Fcgrt, maps to chromosome 7 and thus is not encoded by the MHC. Kandil et al. (1996) showed by fluorescence in situ hybridization that the human gene, FCGRT, maps to 19q13.3. Thus, like its mouse counterpart, FCGRT is not encoded by the MHC.
Akilesh et al. (2004) showed that mice lacking FcRn were resistant to transient inflammatory arthritis induced in wildtype mice upon transfer of serum from arthritic K/BxN mice, which are universally susceptible to autoimmune arthritis due to pathogenic anti-GPI (172400) IgG antibodies. K/BxN mice deficient in FcRn had significantly delayed onset of arthritis or only intermittent ankle inflammation without arthritic disease, and they had low anti-GPI antibody titers without high B-cell levels in popliteal lymph nodes during the experimental period. Heterozygote and sick homozygote mice had lymphocytes expressing the B-cell maturation markes Prdm1 (603423) and Tnfrsf17 (109545), the Th2 cytokines IL1b (147720) and IL10 (124092), the chemokines Scya20 (CCL20; 601960) and Scya3 (CCL3; 182283), and Fcgr1 (146760). Treatment of mice with high-dose intravenous Ig (IVIg) reduced or eliminated arthritis dependent on the presence of Fcgr2 (146790) and/or FcRn. Akilesh et al. (2004) concluded that these findings provide a rational basis for the use of IVIg and suggested that FcRn is a potential therapeutic target linking the initiation and effector phases of humoral autoimmune disease.
In contrast to rodents, in humans FcRn is expressed in adults, in placenta--where it serves to transport IgG from mother to fetus (Story et al., 1994)--and in several absorptive epithelial tissues, including the lung, kidney, and intestine. The expression of FcRn in absorptive epithelia, coupled with the description by Dickinson et al. (1999) of FcRn transport of IgG through human intestinal epithelial cells in vitro, suggested to Bitonti et al. (2004) that FcRn might be exploited for the delivery of therapeutic proteins by conjugation of the proteins to an FcRn-binding ligand, such as the Fc fragment of IgG1, which would allow their transport across the epithelium. Bitonti et al. (2004) showed that FcRn-mediated transport is functional in the lung of nonhuman primates and that this transport system can be used to deliver erythropoietin (EPO; 133170) when it is conjugated to the Fc region of IgG1. Erythropoietin is a hormone used to stimulate red blood cell production but requiring chronic therapy with either intravenous or subcutaneous injection, making an alternative noninvasive method of delivery desirable. FcRn-dependent absorption was more efficient when the EPO-Fc fusion protein was deposited predominantly in the upper and central airways of the lung, where epithelial expression FcRn was most prominently detected. The bioavailability of an EPO-Fc monomer when delivered through the lung was approximately equal to that reported for unconjugated EPO delivered subcutaneously in humans. These studies showed that FcRn can be harnessed to noninvasively deliver bioactive proteins into the systemic circulation in therapeutic quantities.
Ahouse, J. J., Hagerman, C. L., Mittal, P., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Simister, N. E. Mouse MHC class I-like Fc receptor encoded outside the MHC. J. Immun. 151: 6076-6088, 1993. [PubMed: 7504013]
Akilesh, S., Petkova, S., Sproule, T. J., Shaffer, D. J., Christianson, G. J., Roopenian, D. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J. Clin. Invest. 113: 1328-1333, 2004. [PubMed: 15124024] [Full Text: https://doi.org/10.1172/JCI18838]
Bitonti, A. J., Dumont, J. A., Low, S. C., Peters, R. T., Kropp, K. E., Palombella, V. J., Stattel, J. M., Lu, Y., Tan, C. A., Song, J. J., Garcia, A. M., Simister, N. E., Spiekermann, G. M., Lencer, W. I., Blumberg, R. S. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc. Nat. Acad. Sci. 101: 9763-9768, 2004. [PubMed: 15210944] [Full Text: https://doi.org/10.1073/pnas.0403235101]
Dickinson, B. L., Badizadegan, K., Wu, Z., Ahouse, J. C., Zhu, X., Simister, N. E., Blumberg, R. S., Lencer, W. I. Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J. Clin. Invest. 104: 903-911, 1999. [PubMed: 10510331] [Full Text: https://doi.org/10.1172/JCI6968]
Junghans, R. P., Anderson, C. L. The protection receptor for IgG catabolism is the beta-2-microglobulin-containing neonatal intestinal transport receptor. Proc. Nat. Acad. Sci. 93: 5512-5516, 1996. [PubMed: 8643606] [Full Text: https://doi.org/10.1073/pnas.93.11.5512]
Junghans, R. P., Ebralidze, A., Tiwari, B. Does (CUG)n repeat in DMPK mRNA 'paint' chromosome 19 to suppress distant genes to create the diverse phenotype of myotonic dystrophy? A new hypothesis of long-range cis autosomal inactivation. Neurogenetics 3: 59-67, 2001. [PubMed: 11354827] [Full Text: https://doi.org/10.1007/s100480000103]
Kandil, E., Egashira, M., Miyoshi, O., Niikawa, N., Ishibashi, T., Kasahara, M. The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3. Cytogenet. Cell Genet. 73: 97-98, 1996. Note: Erratum: Cytogenet. Cell Genet. 81: 179 only, 1998. [PubMed: 8646894] [Full Text: https://doi.org/10.1159/000134316]
Story, C. M., Mikulska, J. E., Simister, N. E. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J. Exp. Med. 180: 2377-2381, 1994. [PubMed: 7964511] [Full Text: https://doi.org/10.1084/jem.180.6.2377]
Waldmann, T. A., Strober, W. Metabolism of immunoglobulins. Prog. Allergy 13: 1-110, 1969. [PubMed: 4186070] [Full Text: https://doi.org/10.1159/000385919]