Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor genes (PROKR1 (PKR1) and PROKR2 (PKR2)) play an important role in human early pregnancy. We have previously shown that PROKR1 and PROKR2 are associated with recurrent miscarriage (RM) using the tag-SNP method. In this study, we aimed to identify PROKR1 and PROKR2 variants in idiopathic RM patients by genotyping of the entire coding regions. Peripheral blood DNA samples of 100 RM women and 100 controls were subjected to sequence the entire exons of PROKR1 and PROKR2. Significant non-synonymous variant genotypes present in the original 200 samples were further confirmed in the extended samples of 144 RM patients and 153 controls. Genetic variants that were over- or underrepresented in the patients were ectopically expressed in HEK293 and JAR cells to investigate their effects on intracellular calcium influx, cell proliferation, cell invasion, cell-cell adhesion, and tube organization.We found that the allele and genotype frequencies of PROKR1 (I379V) and PROKR2 (V331M) were significantly increased in the normal control groups compared with idiopathic RM women (P<0.05). PROKR1 (I379V) and PROKR2 (V331M) decreased intracellular calcium influx but increased cell invasiveness (P<0.05), whereas cell proliferation, cell-cell adhesion, and tube organization were not significantly affected. In conclusion, PROKR1 (I379V) and PROKR2 (V331M) variants conferred lower risk for RM and may play protective roles in early pregnancy by altering calcium signaling and facilitating cell invasiveness.
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