GnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in KISS1/Kiss1
Open accessAbstract
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. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.
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Kisspeptin and neurokinin B are essential for pubertal development and fertility in humans.
“Moreover, two of the peptides in the hypertrophied neurons, kisspeptin and neurokinin B, are essential for pubertal development and fertility in the human (Chan et al., 2011; Topaloglu et al., 2009, 2012).”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Chan et al., 2011
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- Authors
- Chan, Y.-M., Broder-Fingert, S., Paraschos, S., Lapatto, R., Au, M., Hughes, V., Bianco, S. D. C., Min, L., Plummer, L., Cerrato, F., De Guillebon, A., Wu, I.-H., Wahab, F., Dwyer, A., Kirsch, S., Quinton, R., Cheetham, T., Ozata, M., Ten, S., Chanoine, J.-P., Pitteloud, N., Martin, K. A., Schiffmann, R., Van der Kamp, H. J., Nader, S., Hall, J. E., Kaiser, U. B., & Seminara, S. B.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- University of Toronto (CA)
- Newcastle University (GB)
- Maimonides Medical Center (US)
- University of British Columbia (CA)
- Baylor University Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2011-11
- Volume
- 96
- Issue
- 11
- Pages
- E1771-E1781
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3205899
- OpenAlex
- W1999912381
- Cited by
- 68
- References
- 45
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 8 · 2017: 1 · 2016: 6 · 2015: 10 · 2014: 4 · 2013: 7 · 2012: 6
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007529)
- National Center for Research Resources (M01RR001066, M01-RR01066)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD015788, K08HD070957, R01HD043341, K12HD051959, K24HD067388, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- KISS1, kisspeptin, GnRH deficiency, kisspeptin receptor, rare variants, heterozygous mutation, inositol phosphates, anogenital distance, estrous cycle, litter size, mouse model, KISS1R, hypogonadism, reproductive disorders, variant pathogenicity prediction
- MeSH terms
- Adult, Animals, Female, Genotype, Heterozygote, Humans, Gonadotropin-Releasing Hormone, Male, Phenotype, Mice, Kisspeptins
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