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.
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.
|Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H et al. (2015) Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab 100:E1378-85|
|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|
|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|
|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|
|Abel, Brent S; Shaw, Natalie D; Brown, Jenifer M et al. (2013) Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 98:E206-16|
|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|
|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|
|Chew, Sheena; Balasubramanian, Ravikumar; Chan, Wai-Man et al. (2013) A novel syndrome caused by the E410K amino acid substitution in the neuronal ?-tubulin isotype 3. Brain 136:522-35|
|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|
|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|
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