Mutations inProkineticin 2andProkineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum
| Autor: | Qun-Yong Zhou, Chengkang Zhang, Guy VanVliet, Richard Quinton, Lindsay W. Cole, Andrew A. Dwyer, Duarte Pignatelli, Lacey Plummer, Simon Pearce, Céline Huot, Virginia A. Hughes, Phyllis W. Speiser, Nathalie Alos, Akira Takeshita, William F. Crowley, Frances J. Hayes, Nelly Pitteloud, Stephanie B. Seminara, Yisrael Sidis, Taneli Raivio |
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| Rok vydání: | 2008 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Adolescent Genotype Receptors Peptide Kallmann syndrome Endocrinology Diabetes and Metabolism DNA Mutational Analysis Clinical Biochemistry Mutation Missense CHO Cells Gonadotropin-releasing hormone Biology Transfection Models Biological Biochemistry Receptors G-Protein-Coupled Gastrointestinal Hormones Gonadotropin-Releasing Hormone Genetic Heterogeneity Aequorin Cricetulus Endocrinology Gene Frequency Hypogonadotropic hypogonadism Cricetinae Internal medicine Molecular genetics medicine Animals Humans Missense mutation Hypogonadism Neuropeptides Biochemistry (medical) HEK 293 cells Prokineticin receptor 2 Kallmann Syndrome medicine.disease Prokineticin Pedigree nervous system Female Original Article hormones hormone substitutes and hormone antagonists |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 93:3551-3559 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2007-2654 |
| Popis: | 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.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.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.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.Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH. |
| Databáze: | OpenAIRE |
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