Mutations in Prokineticin 2 and Prokineticin receptor 2 genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum
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CONTEXT: Mice deficient in prokineticin 2(PROK2) and prokineticin receptor2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency. OBJECTIVES: We aimed to screen a large cohort of patients with Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutant alleles in vitro. DESIGN: Sequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using early growth response 1-luciferase assays in HEK 293 cells and aequorin assays in Chinese hamster ovary cells. RESULTS: Four heterozygous and one homozygous PROK2 mutation (p.A24P, p.C34Y, p.I50M, p.R73C, and p.I55fsX1) were identified in five probands. Four probands had KS and one nIHH, and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. There were 11 patients who carried a heterozygous PROKR2 mutation (p.R85C, p.Y113H, p.V115M, p.R164Q, p.L173R, p.W178S, p.S188L, p.R248Q, p.V331M, and p.R357W). Among them, six had KS, four nIHH, and one KS proband carried both a PROKR2 (p.V115M) and PROK2 (p.A24P) mutation. Reproductive phenotypes ranged from absent to partial puberty to complete reversal of GnRH deficiency after discontinuation of therapy. All mutant alleles appear to decrease intracellular calcium mobilization; seven exhibited decreased MAPK signaling, and six displayed decreased receptor expression. Nonreproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Finally, considerable variability was evident in family members with the same mutation, including asymptomatic carriers. CONCLUSION: Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.
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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 [29]
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 [29]
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 [29]
Human mutations in PROK2 and PROKR2 have been found in the heterozygous, homozygous, or compound heterozygous state.
“Human mutations in PROK2 and PROKR2 have been found in the heterozygous, homozygous, or compound heterozygous state.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [29]
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- Authors
- Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., VanVliet, G., Pearce, S., Crowley, W. F., Zhou, Q.-Y., & Pitteloud, N.
- Affiliations
- Harvard University (US)
- University of California, Irvine (US)
- Newcastle University (GB)
- Universidade do Porto (PT)
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine (C.H., N.A.), Montreal, Quebec, H3T 1C5, Canada
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Schneider Children's Hospital (US)
- Toranomon Hospital (JP)
- Endocrinology Service (G.V.V.), Sainte Justine Hospital, Montréal, Québec, Canada H3T 1C5
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-09-01
- Volume
- 93
- Issue
- 9
- Pages
- 3551-3559
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2567850
- OpenAlex
- W2162401422
- Cited by
- 208
- References
- 35
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 11 · 2021: 19 · 2020: 12 · 2019: 4 · 2018: 5 · 2017: 11 · 2016: 11 · 2015: 16 · 2014: 16 · 2013: 16 · 2012: 11
- FWCI
- 21.69
- 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)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD015788, U54HD029164, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- prokineticin 2, PROKR2, GnRH deficiency, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, loss-of-function mutations, genotype-phenotype correlation, calcium mobilization, MAPK signaling, puberty onset, fibrous dysplasia, epilepsy, synkinesis
- MeSH terms
- Adolescent, Aequorin, Animals, Cricetulus, DNA Mutational Analysis, Female, Gastrointestinal Hormones, Gene Frequency, Genotype, Cricetinae, Humans, Hypogonadism, Gonadotropin-Releasing Hormone, Male, Models, Biological, Neuropeptides, Pedigree, Transfection, CHO Cells, Kallmann Syndrome, Receptors, Peptide, Genetic Heterogeneity, Mutation, Missense, Receptors, G-Protein-Coupled
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