Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome
Abstract
Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.
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Frameshift mutations that inactivate PK2 have been reported in sporadic Kallmann syndrome and in families with Kallmann syndrome or normosmic IHH.
“Frameshift mutations that inactivate PK2 have been reported in sporadic cases of Kallmann syndrome28 and in families with a history of Kallmann syndrome or normosmic IHH.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [28]
The Arg73Cys substitution in PK2 greatly reduces activation of PK-R2-mediated calcium signaling and is predicted to disrupt a disulfide bond.
“A single amino acid substitution in PK2 (Arg73Cys) that greatly reduces activation of PK-R2-mediated stimulation of calcium signaling is predicted to disrupt a disulfide bond.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [28]
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 [28]
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- Authors
- Leroy, C., Fouveaut, C., Leclercq, S., Jacquemont, S., Boullay, H. D., Lespinasse, J., Delpech, M., Dupont, J.-M., Hardelin, J.-P., & Dodé, C.
- Affiliations
- Hôpital Cochin (FR)
- Centre Hospitalier Universitaire Vaudois (CH)
- Inserm (FR)
- Corresponding author
- Dodé, Catherine
- Venue
- European Journal of Human Genetics
- Published
- 2008-02-20
- Volume
- 16
- Issue
- 7
- Pages
- 865-868
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W2040183641
- Cited by
- 48
- References
- 16
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 5 · 2012: 1
- FWCI
- 7.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-05)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- Kallmann syndrome, prokineticin 2, biallelic variants, homozygous mutation, hypogonadotropic hypogonadism, anosmia, PROKR2, KAL1, missense mutations, frameshift mutation, digenic inheritance, sporadic cases
- MeSH terms
- Adolescent, Adult, Alleles, Animals, DNA Mutational Analysis, Female, Gastrointestinal Hormones, Humans, Male, Mutation, Neuropeptides, Pedigree, Kallmann Syndrome, Mice
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