Mutations in Prokineticin 2 and Prokineticin Receptor 2 Genes in Human Gonadotrophin-releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2008 Jun 19

PMID 18559922

Citations 108

Authors

Lindsay W Cole

Yisrael Sidis

Chengkang Zhang

Richard Quinton

Lacey Plummer

Duarte Pignatelli

Virginia A Hughes

Andrew A Dwyer

Taneli Raivio

Frances J Hayes

Stephanie B Seminara

Celine Huot

Nathalie Alos

Phyllis Speiser

Akira Takeshita

Guy Van Vliet

Simon Pearce

William F Crowley Jr

Qun-Yong Zhou

Nelly Pitteloud

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Genetic Polymorphisms of Prokineticins and Prokineticin Receptors Associated with Human Disease.

Lattanzi R, Miele R Life (Basel). 2024; 14(10).

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Intracerebroventricular PROK2 infusion could increase the secretion of male reproductive hormones by stimulating the HPG axis.

Yilmaz N, Yildiz A Mol Biol Rep. 2024; 51(1):656.

PMID: 38740671 DOI: 10.1007/s11033-024-09604-4.

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases.

Vincenzi M, Kremic A, Jouve A, Lattanzi R, Miele R, Benharouga M Pharmacol Rev. 2023; 75(6):1167-1199.

PMID: 37684054 PMC: 10595023. DOI: 10.1124/pharmrev.122.000801.

Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency.

Kardelen A, Najafli A, Bas F, Karaman B, Toksoy G, Poyrazoglu S J Clin Res Pediatr Endocrinol. 2023; 15(4):338-347.

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Genetic variants of G-protein coupled receptors associated with pubertal disorders.

Suzuki E, Miyado M, Kuroki Y, Fukami M Reprod Med Biol. 2023; 22(1):e12515.

PMID: 37122876 PMC: 10134480. DOI: 10.1002/rmb2.12515.

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