A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor α-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.