FCGRT

Official Full Name

Fc gamma receptor and transporter

Organism

Homo sapiens

Gene ID

2217

Background

This gene encodes a receptor that binds the Fc region of monomeric immunoglobulin G. The encoded protein transfers immunoglobulin G antibodies from mother to fetus across the placenta. This protein also binds immunoglobulin G to protect the antibody from degradation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Synonyms

FCRN; FcgammaRn; alpha-chain

Bio Chemical Class

Immunoglobulin

Protein Sequence

MGVPRPQPWALGLLLFLLPGSLGAESHLSLLYHLTAVSSPAPGTPAFWVSGWLGPQQYLSYNSLRGEAEPCGAWVWENQVSWYWEKETTDLRIKEKLFLEAFKALGGKGPYTLQGLLGCELGPDNTSVPTAKFALNGEEFMNFDLKQGTWGGDWPEALAISQRWQQQDKAANKELTFLLFSCPHRLREHLERGRGNLEWKEPPSMRLKARPSSPGFSVLTCSAFSFYPPELQLRFLRNGLAAGTGQGDFGPNSDGSFHASSSLTVKSGDEHHYCCIVQHAGLAQPLRVELESPAKSSVLVVGIVIGVLLLTAAAVGGALLWRRMRSGLPAPWISLRGDDTGVLLPTPGEAQDADLKDVNVIPATA

Open

Disease

Acquired haemolytic anaemia, Idiopathic inflammatory myopathy, Inflammatory polyneuropathy, Lupus erythematosus, Myasthenia gravis, Myasthenia gravis, Rheumatoid arthritis, Sjogren syndrome

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

Cat.No.	Product Name	Price
CSC-DC005643	Panoply™ Human FCGRT Knockdown Stable Cell Line	Inquiry
CSC-SC005643	Panoply™ Human FCGRT Over-expressing Stable Cell Line	Inquiry
CSC-RT0672	Human FCGRT Knockout Cell Line-HEK293T	Inquiry
CSC-RO0151	Human FCGRT Stable Cell Line-CHO-K1	Inquiry
CLKO-0178	FCGRT KO Cell Lysate-HEK293T	Inquiry

Cat.No.	Product Name	Price
AD06152Z	Human FCGRT adenoviral particles	Inquiry
LV12745L	human FCGRT (NM_004107) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH293761	shRNA set against Human FCGRT (NM_004107.4)	Inquiry
SHH293765	shRNA set against Mouse FCGRT (NM_010189.3)	Inquiry
SHH293769	shRNA set against Rat FCGRT (NM_033351.2)	Inquiry

Cat.No.	Product Name	Price
MiUTR3H-04120	FCGRT miRNA 3'UTR clone	Inquiry
MiUTR3H-04121	FCGRT miRNA 3'UTR clone	Inquiry
SKO0090	FCGRT Validated sgRNA vector	Inquiry
CDCB156919	Rat FCGRT ORF clone (NM_033351.1)	Inquiry
CDCB156926	Cynomolgus FCGRT ORF clone	Inquiry
CDCB180671	Rabbit FCGRT ORF clone (NM_001122937.1)	Inquiry
CDCL184208	Human FCGRT ORF clone(NM_001136019.2)	Inquiry
CDCL184209	Mouse FCGRT ORF clone(NM_010189.3)	Inquiry

Detailed Information

The neonatal Fc receptor (FcRn) is a critical protein that plays a fundamental role in maintaining body immunoglobulin G (IgG) homeostasis. Expressed in many cells, especially endothelial cells, this receptor shields IgG from lysosomal breakdown and increases its half-life by recycling it back into circulation. FcRn also helps to generate passive immunity by mediating the IgG transfer from mother to fetus. The purpose of FcRn, its participation in immunoglobulin therapy (such as intravenous immunoglobulin [IVIg], and how genetic variances in the FCGRT gene, which codes the FcRn protein, may influence treatment outcomes in autoimmune neurological illnesses are investigated in this review.

FcRn Mechanism and Significance for IgG Homeostasis

Binding the Fc region of IgG is accomplished by a cell surface receptor called FcRn. Comprising an alpha chain (encoded by the FCGRT gene) and a beta-2-microglobulin component, it has structural parallels with important histocompatibility complex (MHC) class I molecules. FcRn's main goal is to attach to IgG in acidic endosomes preventing its breakdown. The complex then finds its way back to the cell surface, where IgG is liberated once more into the bloodstream.

This mechanism considerably increases the half-life of IgG in the circulation. IgG helps to control immune systems and offers protection against poisons and infections in blood. Because of FcRn's recycling process, another important protein in the blood, albumin, also has a long half-life and is protected similarly by FcRn. FcRn is a necessary component of humoral immunity since it can shield IgG from lysosomal breakdown, therefore promoting constant antibody presence in the bloodstream.

This figure illustrates the recycling process of the neonatal Fc receptor (FcRn), which extends the circulation time of Fc- and albumin-fusion protein drugs by recycling receptor-bound proteins back into the bloodstream. Figure 1. FcRn recycling mechanism (Mitragotri S, et al., 2014)

The Role of FCGRT Polymorphisms in Immunoglobulin Therapy

The FCGRT gene, located on chromosome 19, encodes the alpha chain of FcRn. Variations in this gene, specifically in the form of Variable Number of Tandem Repeats (VNTR) polymorphisms, influence the expression levels of FcRn. There are five primary VNTR alleles—VNTR1 through VNTR5—and VNTR3 is the most often occurring. Higher promoter activity displayed by homozygous VNTR3/3 individuals increases FcRn expression as compared to other genotypes, such as VNTR 2 or VNTR3/2.

Clinically, this genetic variety is important, particularly for patients undergoing monoclonal antibodies or intravenous immunoglobulin (IVIg). The recycling mechanism changes when the FcRn is saturated by supraphysiological quantities of IgG, therefore degrading endogenous IgG. When FcRn is over-saturated, IVIg therapy's efficacy may be lowered since endogenous IgG is not recycled as effectively, therefore perhaps requiring higher doses of infused IgG to reach therapeutic levels.

Up to 30% of individuals with several autoimmune neurological illnesses, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), or multifocal motor neuropathy, exhibit no response to traditional IVIg therapy according to research. Variations in the FCGRT genotype, more especially the VNTR3/2 polymorphism, are hypothesized to be responsible for this lack of response by changing the pharmacokinetics (PK) of IgG, hence affecting its half-life and distribution in the body. This hereditary component could assist in explaining why some individuals need much larger IVIg doses for efficient therapy.

FcRn and the Future of Targeted Therapeutics

The understanding of FcRn's role in IgG homeostasis has led to the development of targeted therapies designed to modulate its function. Using monoclonal antibodies that block FcRn will help to stop IgG from recycling and hasten its clearance. Currently, clinical studies for treating antibody-mediated neurological illnesses are these FcRn inhibitors: efgartigimod, rozanolizumab, and nipocalimab.

Particularly in disorders like generalized myasthenia gravis (gMG) and immune thrombocytopenic purpura (ITP), these medicines have shown tremendous promise, especially in conditions when pathogenic autoantibodies play a prominent role. These medications provide a fresh way to treat autoimmune illnesses by lowering pathogenic IgG levels in circulation by blocking FcRn. FcRn inhibitors also may specifically target IgG4 subclass antibodies, which are frequently associated with autoimmune diseases, hence improving their therapeutic value.

Moreover, the role of FcRn in the blood-brain barrier (BBB) has garnered attention, as endothelial cells in the BBB express FcRn. This expression implies that FcRn inhibitors might also be useful in treating disorders involving the central nervous system (CNS). FcRn inhibition could offer a strategy to lower pathogenic IgG levels and enhance disease outcomes in conditions like myasthenia gravis, where IgG autoantibodies attack neuromuscular junctions.

References:

Dalakas MC, Spaeth PJ. The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors. Ther Adv Neurol Disord. 2021 Feb 26;14:1756286421997381.
Zhao X, Zhang G, et al. The Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B. Cell. 2019 May 30;177(6):1553-1565.e16.
Mitragotri S, Burke PA, et al. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655-672.

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