This Article Full Text Full Text (PDF) All Versions of this Article: 93/9/3551    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Cole, L. W. Articles by Pitteloud, N. PubMed PubMed Citation Articles by Cole, L. W. Articles by Pitteloud, N. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Genetics Home Reference Related Collections Neuroendocrinology and Pituitary Male Endocrinology

Mutations in Prokineticin 2 and Prokineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

Reproductive Endocrine Unit of the Department of Medicine (L.W.C., Y.S., L.P., V.A.H., A.A.D., T.R., F.J.H., S.B.S., W.F.C., N.P.), Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114; Department of Pharmacology (C.Z., Q.-Y.Z.), University of California, Irvine, Irvine, California 92697; The Institute for Human Genetics & the School of Clinical Medical Sciences (R.Q.), University of Newcastle-on-Tyne, Newcastle on Tyne NE1 4LP, United Kingdom; Endocrinology Department (D.P., S.P.), San João Hospital, Laboratory of Cell and Molecular Biology, Faculty of Medicine of Porto, and The Institute of Molecular Pathology and Immunology of the University of Porto, 4200–319 Porto, Portugal; Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine (C.H., N.A.), Montreal, Quebec, H3T 1C5, Canada; Division of Pediatric Endocrinology (P.S.), Schneider Children’s Hospital, New Hyde Park, New York 11040; Endocrine Center (A.T.), Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo 105-8470, Japan; and Endocrinology Service (G.V.V.), Sainte Justine Hospital, Montréal, Québec, Canada H3T 1C5

Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., The Harvard Center for Reproductive Endocrine Sciences and the Reproductive Endocrine Unit of the Department of Medicine, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: npitteloud{at}partners.org.

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.