A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter.
The neonatal Fc receptor, FcRn, plays a central role in immunoglobulin G (IgG) transport across placental barriers. Genetic variations of FcRn-dependent transport across the placenta may influence antibody-mediated pathologies of the fetus and the newborn. Sequencing analysis of 20 unrelated individuals demonstrated no missense mutation within the five exons of the FcRn gene. However, a variable number of tandem repeats (VNTR) region within the FcRn promoter was observed, consisting of five different alleles (VNTR1-VNTR5). Alleles with two (VNTR2) and three (VNTR3) repeats were found to be most common in Caucasians (7.5 and 92.0%, respectively). Real-time polymerase chain reaction revealed that monocytes from VNTR3 homozygous individuals express 1.66-fold more FcRn transcript than do monocytes from VNTR2/VNTR3 heterozygous individuals (P = 0.002). In reporter plasmid assays, the VNTR3 allele supported the transcription of a reporter gene twice as effectively as did the VNTR2 allele (P = 0.003). Finally, under acidic conditions, monocytes from VNTR3 homozygous individuals showed an increased binding to polyvalent human IgG when compared with monocytes from VNTR2/VNTR3 heterozygous individuals (P = 0.021). These data indicate that a VNTR promoter polymorphism influences the expression of the FcRn receptor, leading to different IgG-binding capacities.
Sachs
Ulrich J H
UJ
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany.
Socher
Ines
I
Braeunlich
Christian G
CG
Kroll
Hartmut
H
Bein
Gregor
G
Santoso
Sentot
S
D000483:Alleles; D002478:Cells, Cultured; D015870:Gene Expression; D014644:Genetic Variation; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007231:Infant, Newborn; D009000:Monocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics*; D018709:Statistics, Nonparametric; D020080:Tandem Repeat Sequences; D014158:Transcription, Genetic
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal