PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity
Open accessAbstract
Kallmann syndrome (KS) combines hypogonadism due to gonadotropin-releasing hormone deficiency, and anosmia or hyposmia, related to defective olfactory bulb morphogenesis. In a large series of KS patients, ten different missense mutations (p.R85C, p.R85H, p.R164Q, p.L173R, p.W178S, p.Q210R, p.R268C, p.P290S, p.M323I, p.V331M) have been identified in the gene encoding the G protein-coupled receptor prokineticin receptor-2 (PROKR2), most often in the heterozygous state. Many of these mutations were, however, also found in clinically unaffected individuals, thus raising the question of their actual implication in the KS phenotype. We reproduced each of the ten mutations in a recombinant murine Prokr2, and tested their effects on the signalling activity in transfected HEK-293 cells, by measuring intracellular calcium release upon ligand-activation of the receptor. We found that all mutated receptors except one (M323I) had decreased signalling activities. These could be explained by different defective mechanisms. Three mutations (L173R, W178S, P290S) impaired cell surface-targeting of the receptor. One mutation (Q210R) abolished ligand-binding. Finally, five mutations (R85C, R85H, R164Q, R268C, V331M) presumably impaired G protein-coupling of the receptor. In addition, when wild-type and mutant receptors were coexpressed in HEK-293 cells, none of the mutant receptors that were retained within the cells did affect cell surface-targeting of the wild-type receptor, and none of the mutant receptors properly addressed at the plasma membrane did affect wild-type receptor signalling activity. This argues against a dominant negative effect of the mutations in vivo.
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Other PROKR2 mutants with substitutions in the first, second and third intracellular loops or carboxyl tail have similarly impaired calcium signaling but normal expression levels and cell surface targeting.
“Other mutants with amino acid substitutions in the first, second and third intracellular loops, or in the carboxyl tail of PK-R2 have similarly impaired calcium signaling but normal expression levels and cell surface targeting.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [32]
In vitro studies show that substitution of Leu173, Trp178, and Pro290 in PROKR2 impairs cell surface targeting, probably because the receptor protein is incorrectly folded.
“In vitro studies have shown that substitution of Leu173, Trp178, and Pro290 in PROKR2 impairs the cell surface targeting of the receptor, probably because the receptor protein is incorrectly folded.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [32]
These PROKR2 mutants probably have impaired G-protein coupling.
“These mutants probably have impaired G-protein coupling.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [32]
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The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
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- Authors
- Monnier, C., Dodé, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., & Rondard, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Hardelin, Jean-Pierre
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-29
- Volume
- 18
- Issue
- 1
- Pages
- 75-81
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3298864
- OpenAlex
- W2158061036
- Cited by
- 123
- References
- 32
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 11 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-05-MRAR-0027)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Keywords
- Kallmann syndrome, PROKR2, missense mutations, G protein-coupled receptor signaling, intracellular calcium release, ligand binding, G protein coupling, anosmia, hypogonadism, dominant negative effect
- MeSH terms
- Amino Acid Sequence, Animals, Calcium, Cell Line, Gastrointestinal Hormones, Humans, Models, Molecular, Neuropeptides, Signal Transduction, Protein Structure, Tertiary, Kallmann Syndrome, Receptors, Peptide, Mutation, Missense, Receptors, G-Protein-Coupled, Mice
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