Kisspeptin is a key hypothalamic neuropeptide controlling virtually every aspect of GnRH neurosecretion in mammals. In humans and rodents, KISS1 invalidation leads to hypogonadotropic hypogonadism (HH). Kisspeptin is also abundantly expressed in the female reproductive tract, notably in syncytiotrophoblast, where clinical and experimental studies indicate crucial roles in decidualization and placentation.

Clinical, biological phenotypes and molecular characterization of two novel homozygous KISS1 mutations from two unrelated families.

In family 1, three brothers presented with typical clinical and hormonal profiles of congenital normosmic HH. Unexpectedly, a reversal with complete and sustained recovery of gonadotropin function and spontaneous spermatogenesis was observed in two of three brothers until up to nine years of follow-up. In family 2, the propositus had HH and accomplished two uneventful pregnancies induced by pulsatile GnRH, with no reported miscarriages. Her second pregnancy was utmost interesting, as either the mother and her son carried the same homozygous frameshift, leading to complete kisspeptin ablation within the fetoplacental unit. The two variants were distinct single nucleotide deletions subjected to nonsense-mediated mRNA decay. Dynamics of transcript analyses from cultured fibroblasts showed almost undetectable KISS1 copies, which increased following treatment by emetine. Western blots conducted on cell lysates transfected by mutagenized KISS1 confirmed the absence of kisspeptin protein.

We report unexpected findings from two families harboring deleterious KISS1 mutations. We demonstrate the dispensability of kisspeptin integrity to maintain either a functional gonadotropic axis in adulthood or to achieve a normal placentation, in humans. These findings prompt revision of the current understandings in human reproductive physiology, and suggest the participation of compensatory pathways to sustain GnRH drive and placental development in the absence of viable kisspeptin, with clear implications for diagnostic purposes, genetic counseling, and therapeutic strategies.