| The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. | |
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MedLine Citation:
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PMID: 21037178 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A widely dispersed network of hypothalamic GnRH neurons controls the reproductive axis in mammals. Genetic investigation of the human disease model of isolated GnRH deficiency has revealed several key genes crucial for GnRH neuronal ontogeny and GnRH secretion. Among these genes, prokineticin 2 (PROK2), and PROK2 receptor (PROKR2) have recently emerged as critical regulators of reproduction in both mice and humans. Both prok2- and prokr2-deficient mice recapitulate the human Kallmann syndrome phenotype. Additionally, PROK2 and PROKR2 mutations are seen in humans with Kallmann syndrome, thus implicating this pathway in GnRH neuronal migration. However, PROK2/PROKR2 mutations are also seen in normosmic GnRH deficiency, suggesting a role for the prokineticin signaling system in GnRH biology that is beyond neuronal migration. This observation is particularly surprising because mature GnRH neurons do not express PROKR2. Moreover, mutations in both PROK2 and PROKR2 are predominantly detected in the heterozygous state with incomplete penetrance or variable expressivity frequently seen within and across pedigrees. In some of these pedigrees, a "second hit" or oligogenicity has been documented. Besides reproduction, a pleiotropic physiological role for PROK2 is now recognized, including regulation of pain perception, circadian rhythms, hematopoiesis, and immune response. Therefore, further detailed clinical studies of patients with PROK2/PROKR2 mutations will help to map the broader biological role of the PROK2/PROKR2 pathway and identify other interacting genes/proteins that mediate its molecular effects in humans. |
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Authors:
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Cecilia Martin; Ravikumar Balasubramanian; Andrew A Dwyer; Margaret G Au; Yisrael Sidis; Ursula B Kaiser; Stephanie B Seminara; Nelly Pitteloud; Qun-Yong Zhou; William F Crowley |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review Date: 2010-10-29 |
Journal Detail:
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Title: Endocrine reviews Volume: 32 ISSN: 1945-7189 ISO Abbreviation: Endocr. Rev. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-06 Completed Date: 2011-07-21 Revised Date: 2013-03-05 |
Medline Journal Info:
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Nlm Unique ID: 8006258 Medline TA: Endocr Rev Country: United States |
Other Details:
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Languages: eng Pagination: 225-46 Citation Subset: IM |
Affiliation:
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Harvard Center for Reproductive Endocrine Sciences, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, 02114, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Gastrointestinal Hormones / genetics, physiology* Humans Mice Mice, Knockout Models, Animal Mutation Neuropeptides / genetics, physiology* Receptors, G-Protein-Coupled / genetics, physiology Receptors, Peptide / genetics, physiology Reproduction / physiology* Signal Transduction / physiology |
| Grant Support | |
ID/Acronym/Agency:
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5R01HD015788/HD/NICHD NIH HHS; 5U54HD028138/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Gastrointestinal Hormones; 0/Neuropeptides; 0/PROK2 protein, human; 0/PROKR2 protein, human; 0/Prok2 protein, mouse; 0/Prokr2 protein, mouse; 0/Receptors, G-Protein-Coupled; 0/Receptors, Peptide |
| Comments/Corrections | |
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