TY - JOUR
T1 - GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1
AU - Chan, Yee Ming
AU - Broder-Fingert, Sarabeth
AU - Paraschos, Sophia
AU - Lapatto, Risto
AU - Au, Margaret
AU - Hughes, Virginia
AU - Bianco, Suzy D.C.
AU - Min, Le
AU - Plummer, Lacey
AU - Cerrato, Felecia
AU - De Guillebon, Adelaide
AU - Wu, I. Hsuan
AU - Wahab, Fazal
AU - Dwyer, Andrew
AU - Kirsch, Susan
AU - Quinton, Richard
AU - Cheetham, Timothy
AU - Ozata, Metin
AU - Ten, Svetlana
AU - Chanoine, Jean Pierre
AU - Pitteloud, Nelly
AU - Martin, Kathryn A.
AU - Schiffmann, Raphael
AU - Van Der Kamp, Hetty J.
AU - Nader, Shahla
AU - Hall, Janet E.
AU - Kaiser, Ursula B.
AU - Seminara, Stephanie B.
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80655148224&partnerID=8YFLogxK
U2 - 10.1210/jc.2011-0518
DO - 10.1210/jc.2011-0518
M3 - Article
C2 - 21880801
AN - SCOPUS:80655148224
SN - 0021-972X
VL - 96
SP - E1771-E1781
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 11
ER -