Infants of Women with Polycystic Ovary Syndrome have Lower Cord Blood Androstenedione and Estradiol Levels

Context: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutationsofitsreceptor(KISS1R)causeisolatedhypogonadotropichypogonadism(IHH).AuniqueKISS1Ractivatingmutationwas described in central precocious puberty (CPP). Objective: To investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH. Patients: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development. Methods: The promoter region and the 3 exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54) and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was pre-incubated in human serum prior to stimulation of the cells. Results:Two novelKISS1missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developedCPPat1yrofage.Thep.H90DmutationwasidentifiedinthehomozygousstateintwounrelatedgirlswithCPP.Invitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild-type. After pre-incubation of wild-type and mutant kp54’s in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared to the wild-type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. Conclusion:TwoKISS1mutationswereidentifiedinunrelatedpatientswithidiopathicCPP.Thep.P74Svariantwasassociatedwith