Inactivating KISS1 mutation and hypogonadotropic hypogonadism

N Engl J Med. 2012 Feb 16;366(7):629-35. doi: 10.1056/NEJMoa1111184.


Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Consanguinity
  • Female
  • Genes, Recessive
  • Genotyping Techniques
  • Gonadotropin-Releasing Hormone / metabolism
  • Humans
  • Hypogonadism / genetics*
  • Kisspeptins / genetics*
  • Male
  • Mutation*
  • Pedigree
  • Puberty / genetics*
  • Sequence Analysis, DNA


  • KISS1 protein, human
  • Kisspeptins
  • Gonadotropin-Releasing Hormone