GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1

Yee Ming Chan, Sarabeth Broder-Fingert, Sophia Paraschos, Risto Lapatto, Margaret Au, Virginia Hughes, Suzy D.C. Bianco, Le Min, Lacey Plummer, Felecia Cerrato, Adelaide De Guillebon, I. Hsuan Wu, Fazal Wahab, Andrew Dwyer, Susan Kirsch, Richard Quinton, Timothy Cheetham, Metin Ozata, Svetlana Ten, Jean Pierre ChanoineNelly Pitteloud, Kathryn A. Martin, Raphael Schiffmann, Hetty J. Van Der Kamp, Shahla Nader, Janet E. Hall, Ursula B. Kaiser, Stephanie B. Seminara

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Context: KISS1 is a candidate gene for GnRH deficiency. Objective: Our objective was to identify deleterious mutations in KISS1. Patients and Methods: DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions. Results: Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r 2 = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice. Conclusions: Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. Asin Kiss1 +/-/Kiss1r +/-mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Original languageEnglish (US)
Pages (from-to)E1771-E1781
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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