Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy

Abstract

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.

Gene-gene interactions and risk of recurrent miscarriages in carriers of endocrine gland–derived vascular endothelial growth factor and prokineticin receptor polymorphisms

“…The detected PROKR1 and PROKR2 variants were described in our previous study (21) (work reproduction permitted by Reproduction). We detected seven variants (S40G, G77S, L93L, P169P, A194S, F314F, and I379V) in the PROKR1 coding region and ten (A51T, F50F, L127R, V131I, Y140C, L155L, T195T, V331M, N370N, and T374T) in the PROKR2 coding region.…”

“…A total of 142 women who had experienced at least two consecutive spontaneous abortions were recruited from outpatient clinics of our hospital. All subjects had undergone a comprehensive examination, as described in our previous publications (21,23). Women with any identifiable cause of RM were excluded from the study.…”

“…PROKR1 and PROKR2 variant detection was carried out as previously described (21). The EG-VEGF gene is located on 1p21 (Genbank accession no.…”

“…PROKR1 and PROKR2 are differentially and temporally expressed in different parts of female reproductive tissues, including the ovaries, endometrium, and placenta (11,19). Their dysregulation or polymorphisms have been associated with ectopic pregnancy, RM, and preeclampsia (20)(21)(22). Although these two GPCRs are thought to have important and different effects on human early pregnancy, their exact roles in reproduction remain to be characterized.…”

Prokinéticines

“…Concernant l'implantation embryonnaire, plusieurs publications ont conclu à une augmentation des prokinéticines dans les grossesses ectopiques [24], ainsi que dans les fausses couches répétées [25,26]. Récemment, certaines variations de la séquence nucléotidique des gènes PROK1, PROKR1, et PROKR2 ont été associées aux fausses couches répétées [25], alors que d'autres variants semblent, au contraire, avoir un rôle protecteur aux stades précoces de la grossesse [27]. Le système PROK1/PROKR a été décrit comme un acteur important du développement placentaire [8].…”