Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2
Open accessAbstract
Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
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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 [27]
In a study of 192 patients with Kallmann syndrome, 10 PROKR2 mutations were identified, five of which resulted in single amino acid substitutions in transmembrane domains.
“In a study of 192 patients with Kallmann syndrome, 10 mutations in PROKR2 were identified,27 five (50%) of which resulted in single amino acid substitutions in the transmembrane domains (Leu173Arg, Trp178Ser, Pro290Ser, Met323Ile, and Val331Met).”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [27]
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 [27]
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 [27]
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- Authors
- Dodé, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., & Hardelin, J.-P.
- Affiliations
- Inserm (FR)
- Hôpital Cochin (FR)
- Hôpital Saint-Antoine (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Hôpital Universitaire Dupuytren (FR)
- Centre Hospitalier Universitaire Amiens-Picardie (FR)
- Hôpital Jeanne de Flandre (FR)
- Hôpital Saint-Vincent-de-Paul (FR)
- Bicêtre Hospital (FR)
- Corresponding author
- Dodé, Catherine
- Hardelin, Jean-Pierre
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-10-20
- Volume
- 2
- Issue
- 10
- Pages
- e175
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W2003282533
- Cited by
- 457
- References
- 33
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 12 · 2023: 18 · 2022: 19 · 2021: 28 · 2020: 21 · 2019: 18 · 2018: 13 · 2017: 21 · 2016: 17 · 2015: 31 · 2014: 27 · 2013: 30 · 2012: 30
- FWCI
- 26.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Agence Nationale de la Recherche (ANR-05)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- Kallmann syndrome, prokineticin 2, PROKR2, anosmia, olfactory bulb development, hypogonadism, gonadotropin-releasing hormone deficiency, KAL1, FGFR1, digenic inheritance, compound heterozygosity, genetic transmission
- MeSH terms
- Chromosomes, Human, Exons, Female, Gastrointestinal Hormones, Humans, Male, Mutation, Neuropeptides, Pedigree, Cohort Studies, Kallmann Syndrome, Receptors, Peptide, Chromosome Segregation, Receptors, G-Protein-Coupled
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