Mutations of the KISS1 gene in disorders of puberty

Silveira, L. G.; Noel, S. D.; Silveira-Neto, A. P.; Abreu, A. P.; Brito, V. N.; Santos, M. G.; Bianco, S. D. C.; Kuohung, W.; Xu, S.; Gryngarten, M.; Escobar, M. E.; Arnhold, I. J. P.; Mendonca, B. B.; Kaiser, U. B.; Latronico, A. C.

doi:10.1210/jc.2009-2421

Cited by 352Hypothalamic control of reproductive hormonesGrowth Hormone and Insulin-like Growth FactorsNeuropeptides and Animal Physiology

Mutations of the KISS1 gene in disorders of puberty

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Silveira, L. G., Noel, S. D., Silveira-Neto, A. P., Abreu, A. P., Brito, V. N., Santos, M. G., Bianco, S. D. C., Kuohung, W. +7 more·2010·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2009-2421PMC PMC2869552

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CONTEXT: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP). OBJECTIVE: Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH. PATIENTS: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development. METHODS: The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells. RESULTS: Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group. CONCLUSION: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype.

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Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.
“Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.47,48”
From Pubertal development and regulation (2016) · cites this paper as [48]

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“Loss-of-function mutations of the kisspeptin receptor (GPR54 or KISS1R) cause normosmic IHH(9,10).”
Background
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Research works printed but not linked: 1

[20]20. **Houang M, Roze C, Kaci FM, Yves LB, Carel JC, Leger J, de Roux N** 2009 *KiSS* 1 polymorphisms analysis in a cohort of patients with disorder in the timing of pubertal onset shows association between 3′ UTR polymorphisms and central precocious puberty. Abstract in Hormone Research, Proceedings of the LWPES/ESPE 8th Joint Meeting, 72:49 [[Google Scholar](https://scholar.google.com/scholar_lookup?Houang%20M,%20Roze%20C,%20Kaci%20FM,%20Yves%20LB,%20Carel%20JC,%20Leger%20J,%20de%20Roux%20N%202009%20KiSS%201%20polymorphisms%20analysis%20in%20a%20cohort%20of%20patients%20with%20disorder%20in%20the%20timing%20of%20pubertal%20onset%20shows%20association%20between%203%E2%80%B2%20UTR%20polymorphisms%20and%20central%20precocious%20puberty.%20Abstract%20in%20Hormone%20Research,%20Proceedings%20of%20the%20LWPES/ESPE%208th%20Joint%20Meeting,%2072:49)]

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Διερεύνηση της πιθανής συσχέτισης των επιπέδων της λεπτίνης, της αδιπονεκτίνης και της kisspeptin με τα ωοθηκικά αποθέματα των γυναικών αναπαραγωγικής ηλικίας
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Authors: Silveira, L. G., Noel, S. D., Silveira-Neto, A. P., Abreu, A. P., Brito, V. N., Santos, M. G., Bianco, S. D. C., Kuohung, W., Xu, S., Gryngarten, M., Escobar, M. E., Arnhold, I. J. P., Mendonca, B. B., Kaiser, U. B., & Latronico, A. C.
Affiliations: Unidade de Endocrinologia do Desenvolvimento (L.G.S., A.P.S.-N., A.P.A., V.N.B., M.G.S., I.J.P.A., B.B.M., A.C.L.), Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-900 Brasil
Brigham and Women's Hospital (US)
Universidade de São Paulo (BR)
Hospital General de Niños Ricardo Gutierrez (AR)
ORCID: Brito, V. N.
Santos, M. G.
Bianco, S. D. C.
Kuohung, W.
Xu, S.
Gryngarten, M.
Arnhold, I. J. P.
Mendonca, B. B.
Kaiser, U. B.
Latronico, A. C.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2010-05-01
Volume: 95
Issue: 5
Pages: 2276-2280
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2009-2421
PMC: PMC2869552
OpenAlex: W2144716768
Cited by: 352
References: 20
Citations by year: 2026: 6 · 2025: 19 · 2024: 19 · 2023: 26 · 2022: 25 · 2021: 31 · 2020: 30 · 2019: 24 · 2018: 20 · 2017: 16 · 2016: 22 · 2015: 23 · 2014: 25 · 2013: 21 · 2012: 16
FWCI: 24.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD051959, R21HD059015, U54HD028138)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: KISS1, kisspeptin, kisspeptin receptor, KISS1R, idiopathic central precocious puberty, isolated hypogonadotropic hypogonadism, missense mutations, kisspeptin-54, GnRH secretion, puberty onset, signal transduction
MeSH terms: Receptors, Kisspeptin-1, Exons, Female, Humans, Hypogonadism, Infant, Gonadotropin-Releasing Hormone, Male, Mutation, Penis, Puberty, Puberty, Precocious, Tumor Suppressor Proteins, Receptors, G-Protein-Coupled, Kisspeptins

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Mutations of the KISS1 gene in disorders of puberty

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