Patients with GnRH deficiency exhibit a variety of clinical syndromes including normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH), Kallmann's Syndrome (KS) and Acquired Hypogonadotropic Aypogonadism (AHH). These conditions have in common that they permit discovery of a series of genetic defects in the ontogeny of GnRH neurons. Recently, we discovered that the genes encoding the prokineticin 2 system, specifically the ligand Prokineticin 2 (PROK2) and its receptor Prokineticin (PROKR2), are two new genes crucial for GnRH ontogeny as attested to by the fact that mutations in both of these genes cause nIHH/KS/AHH as do their targeted deletions in mice. In addition, the ligand, PROK2, appears to be an essential link between the reproductive and circadian systems. These patients and their findings thus offer unique biologic opportunities to define the broad spectrum of their reproductive and non-reproductive phenotypes. Using the combined approaches of human investigation, molecular biology, genetics, and targeted gene deletion in mice, we plan to define the complete phenotypic spectrum of defects seen in patients with mutations in either PROK2 or PROKR2. We will then define their biology in vitro, and combine these efforts with animal studies in which gene dosing maybe examined. The novel information forthcoming from patients with mutations in the prokineticin system and the ability to perform targeted gene deletions in mice should enlighten our understanding of GnRH's developmental biology, migratory behavior, role in GnRH function and links with the circadian system.

Public Health Relevance

We plan to investigate the genotype/phenotypes of patients with GnRH deficiency due to mutations in prokineticin 2 (PROK2) and its receptor (PROKR2). We will use the complementary tools of clinical research in humans, targeted gene deletions in mice, biochemistry, and molecular biology to fully elucidate the biology of this system in the human.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD015788-26
Application #
8324982
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
1981-07-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
26
Fiscal Year
2012
Total Cost
$452,224
Indirect Cost
$128,862
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Balasubramanian, Ravikumar; Cohen, Daniel A; Klerman, Elizabeth B et al. (2014) Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2. J Clin Endocrinol Metab 99:E561-6
Xiao, Ling; Zhang, Chengkang; Li, Xiaohan et al. (2014) Signaling role of prokineticin 2 on the estrous cycle of female mice. PLoS One 9:e90860
Sidhoum, Valerie F; Chan, Yee-Ming; Lippincott, Margaret F et al. (2014) Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab 99:861-70
Dwyer, Andrew A; Sykiotis, Gerasimos P; Hayes, Frances J et al. (2013) Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 98:E1790-5
Miraoui, Hichem; Dwyer, Andrew A; Sykiotis, Gerasimos P et al. (2013) Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 92:725-43
Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W et al. (2013) Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab 98:E943-53
Raivio, Taneli; Avbelj, Magdalena; McCabe, Mark J et al. (2012) Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab 97:E694-9
Lewkowitz-Shpuntoff, Hilana M; Hughes, Virginia A; Plummer, Lacey et al. (2012) Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab 97:E136-44
Balasubramanian, Ravikumar; Plummer, Lacey; Sidis, Yisrael et al. (2011) The puzzles of the prokineticin 2 pathway in human reproduction. Mol Cell Endocrinol 346:44-50
Martin, Cecilia; Balasubramanian, Ravikumar; Dwyer, Andrew A et al. (2011) The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev 32:225-46

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