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Cited by 291Hypothalamic control of reproductive hormonesGrowth Hormone and Insulin-like Growth FactorsPituitary Gland Disorders and Treatments

Two Novel Missense Mutations in G Protein-Coupled Receptor 54 in a Patient with Hypogonadotropic Hypogonadism

Semple, R. K., Achermann, J. C., Ellery, J., Farooqi, I. S., Karet, F. E., Stanhope, R. G., O’Rahilly, S., Aparicio, S. A.·2005·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2004-1418
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Abstract

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR)54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.

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  • Although the Arg297Leu mutation only slightly decreased KiSS-1 receptor activity, the combination of Arg297Leu and Cys223Arg was enough to cause hypogonadism.

    “Although the mutation in the other allele—Arg297Leu—only slightly decreased the activity of the KiSS-1 receptor, the combination of the two mutated alleles was enough to cause hypogonadism.”

    From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [52]

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Authors
Semple, R. K., Achermann, J. C., Ellery, J., Farooqi, I. S., Karet, F. E., Stanhope, R. G., O’Rahilly, S., & Aparicio, S. A.
Affiliations
  • University of Cambridge (GB)
  • University College London (GB)
  • Great Ormond Street Hospital (GB)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2005-03
Volume
90
Issue
3
Pages
1849-1855
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2004-1418
OpenAlex
W1967398239
Cited by
291
References
20
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 11 · 2019: 12 · 2018: 10 · 2017: 6 · 2016: 9 · 2015: 19 · 2014: 14 · 2013: 14 · 2012: 17
FWCI
28.06
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (068086, 068061)
  • Raymond and Beverly Sackler Foundation
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
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
GPR54, hypogonadotropic hypogonadism, isolated hypogonadotropic hypogonadism, missense mutations, loss-of-function mutations, G protein-coupled receptor signaling, delayed puberty, compound heterozygosity
MeSH terms
Receptors, Kisspeptin-1, Adolescent, Amino Acid Sequence, Female, Genetic Testing, Humans, Hypogonadism, Male, Molecular Sequence Data, Prevalence, Receptors, Neuropeptide, Mutation, Missense, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled

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