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This version published online on June 17, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-2654
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Submitted on December 3, 2007
Accepted on June 6, 2008

Mutations in Prokineticin 2 (PROK2) and PROK2 Receptor (PROKR2) in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

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, and Nelly Pitteloud*

Reproductive Endocrine Unit of the Department of Medicine, Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 & Harvard Medical School; Department of Pharmacology, University of California, Irvine, Irvine, California 92697; The Institute for Human Genetics & the School of Clinical Medical Sciences, University of Newcastle-on-Tyne, UK; Endocrinology Department, San João Hospital, Laboratory of Cell and Mol. Biology, Faculty of Medicine of Porto, and IPATIMUP, Porto, Portugal; Centre de Recherche du CHU Sainte-Justine, 3175 Cote-St-Catherine, Montreal, Quebec, H3T 1C5, Canada; Division of Pediatric Endocrinology, Schneider Children's Hospital, New York; Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research 2 2 2 Toranomon Tokyo, Japan; Endocrinology Service, Sainte Justine Hospital, 3175 Sainte Catherine Road, Montréal, Québec, H3T 1C5

* To whom correspondence should be addressed. E-mail: npitteloud{at}partners.org.

Context: Mice deficient in Prok2 and 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 with a normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism [nIHH]) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutants alleles in vitro.

Design: Sequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using Egr1-LUC assays in HEK 293 cells and Aequorin assays in CHO cells.

Results: Four heterozygous and one homozygous PROK2 mutations (p.A24P, p.C34Y, p.I50M, p.R73C, p.I55fsX1) were identified in 5 probands. Four probands had KS and one nIHH and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. Eleven patients carried an heterozygous PROKR2 mutation (p.R85C, p.Y113H, p.V115M, p.R164Q, p.L173R, p.W178S, p.S188L, p.R248Q, p.V331M, p.R357W). Among them, 6 had KS, 4 nIHH, and one KS proband carried both a PROKR2 (p.V115M) and PROK2 (p.A24P) mutations. 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. Non-reproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Considerable clinical variability was evident in family members with the same mutation including asymptomatic carriers. Notably,

Conclusions: Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and normosmic IHH.
Key words: GnRH deficiency • prokineticin 2 • prokineticin receptor 2 • Kallmann Syndrome • idiopathic hypogonadotropic hypogonadism






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