Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
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Gonadotropin-releasing hormone (GnRH) deficiency in the human presents either as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or with anosmia [Kallmann syndrome (KS)]. To date, several loci have been identified to cause these disorders, but only 30% of cases exhibit mutations in known genes. Recently, murine studies have demonstrated a critical role of the prokineticin pathway in olfactory bulb morphogenesis and GnRH secretion. Therefore, we hypothesize that mutations in prokineticin 2 ( PROK2 ) underlie some cases of KS in humans and that animals deficient in Prok2 would be hypogonadotropic. One hundred IHH probands (50 nIHH and 50 KS) with no known mutations were examined for mutations in the PROK2 gene. Mutant PROK2s were examined in functional studies, and the reproductive phenotype of the Prok2 −/− mice was also investigated. Two brothers with KS and their sister with nIHH harbored a homozygous deletion in the PROK2 gene (p.[I55fsX1]+[I55fsX1]). Another asymptomatic brother was heterozygous for the deletion, whereas both parents (deceased) had normal reproductive histories. The identified deletion results in a truncated PROK2 protein of 27 amino acids (rather than 81 in its mature form) that lacks bioactivity. In addition, Prok2 −/− mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Homozygous loss-of-function PROK2 mutations cause both KS and nIHH.
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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 [26]
Prok2−/− mice fail to enter puberty, have low gonadotropin levels, and have a significant decrease in hypothalamic GnRH neurons.
“Likewise, Prok2−/− mice fail to enter puberty, have low gonadotropin levels, and have a significant decrease in hypothalamic GnRH neurons.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [26]
GnRH neurons in Prok2−/− mice cross the cribriform plate to enter the central nervous system during embryonic development but do not migrate into and populate the hypothalamus.
“Interestingly, GnRH neurons in Prok2−/− mice were able to cross the cribriform plate (a horizontal plate of the ethmoid bone) to enter the central nervous system during embryonic development, but the neurons did not migrate into and populate the hypothalamus.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [26]
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 [26]
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- Authors
- Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., & Crowley, W. F.
- Affiliations
- Harvard University (US)
- University of California, Irvine (US)
- Universidade do Porto (PT)
- University of California San Diego (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-30
- Volume
- 104
- Issue
- 44
- Pages
- 17447-17452
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2077276
- OpenAlex
- W2090831400
- Cited by
- 264
- References
- 27
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 11 · 2020: 6 · 2019: 16 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 23 · 2014: 20 · 2013: 12 · 2012: 15
- FWCI
- 26.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HD012303)
- National Institute of Mental Health (MH067753, R01MH067753)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044838, DK044838)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD020377, R01HD072754, R01HD015788, P50HD012303, U54HD029164, R01HD020377, U54HD012303, HD 020377, 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 › Growth Hormone and Insulin-like Growth Factors
- Keywords
- prokineticin 2, Kallmann syndrome, GnRH deficiency, loss-of-function mutations, homozygous deletion, truncated protein, GnRH neuron migration, anosmia
- MeSH terms
- Animals, Base Sequence, Cell Movement, Female, Gastrointestinal Hormones, Gene Expression Regulation, Genotype, Humans, Hypogonadism, Gonadotropin-Releasing Hormone, Male, Mutation, Neurons, Neuropeptides, Pedigree, Phenotype, Reproduction, Gene Deletion, Kallmann Syndrome, Mice, Knockout, Mice
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