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http://purl.uniprot.org/citations/18559922http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/18559922http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/18559922http://www.w3.org/2000/01/rdf-schema#comment"

Context

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.

Objectives

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.

Design

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.

Results

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.

Conclusion

Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.org/dc/terms/identifier"doi:10.1210/jc.2007-2654"xsd:string
http://purl.uniprot.org/citations/18559922http://purl.org/dc/terms/identifier"doi:10.1210/jc.2007-2654"xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Alos N."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Alos N."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Zhang C."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Zhang C."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Zhou Q.Y."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Zhou Q.Y."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Takeshita A."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Takeshita A."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Sidis Y."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Sidis Y."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Crowley W.F. Jr."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Crowley W.F. Jr."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Pitteloud N."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Pitteloud N."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Seminara S.B."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Seminara S.B."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Dwyer A.A."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Dwyer A.A."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Hughes V.A."xsd:string
http://purl.uniprot.org/citations/18559922http://purl.uniprot.org/core/author"Hughes V.A."xsd:string
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