title: GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1.
abstract: BACKGROUND
  KISS1 is a candidate gene for GnRH deficiency.
  
  
  OBJECTIVE
  Our objective was to identify deleterious mutations in KISS1.
  
  
  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. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.
authors: Harvard Center for Reproductive Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors: Yee-Ming
authors: YM
authors: Chan
authors: Sarabeth
authors: S
authors: Broder-Fingert
authors: Sophia
authors: S
authors: Paraschos
authors: Risto
authors: R
authors: Lapatto
authors: Margaret
authors: M
authors: Au
authors: Virginia
authors: V
authors: Hughes
authors: Suzy D C
authors: SD
authors: Bianco
authors: Le
authors: L
authors: Min
authors: Lacey
authors: L
authors: Plummer
authors: Felecia
authors: F
authors: Cerrato
authors: Adelaide
authors: A
authors: De Guillebon
authors: I-Hsuan
authors: IH
authors: Wu
authors: Fazal
authors: F
authors: Wahab
authors: Andrew
authors: A
authors: Dwyer
authors: Susan
authors: S
authors: Kirsch
authors: Richard
authors: R
authors: Quinton
authors: Timothy
authors: T
authors: Cheetham
authors: Metin
authors: M
authors: Ozata
authors: Svetlana
authors: S
authors: Ten
authors: Jean-Pierre
authors: JP
authors: Chanoine
authors: Nelly
authors: N
authors: Pitteloud
authors: Kathryn A
authors: KA
authors: Martin
authors: Raphael
authors: R
authors: Schiffmann
authors: Hetty J
authors: HJ
authors: Van der Kamp
authors: Shahla
authors: S
authors: Nader
authors: Janet E
authors: JE
authors: Hall
authors: Ursula B
authors: UB
authors: Kaiser
authors: Stephanie B
authors: SB
authors: Seminara
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency*; D006579:Heterozygote; D006801:Humans; D059648:Kisspeptins / Q000235:genetics*; D008297:Male; D051379:Mice; D010641:Phenotype
chemical_list: C106628:KISS1 protein, human; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D007987:Gonadotropin-Releasing Hormone