The interaction of hypothalamic gonadotropin releasing hormone (GnRH) with pituitary gonadotrophs to produce follicle stimulating hormone (FSH) and luteinizing hormone (LH) represents the principle orchestrating event of normal gonadal function and reproduction in mammals. When gonadotropins are deficient, absent puberty and infertility result in the clinical disorder idiopathic hypogonadotropic hypogonadism (IHH). Although initially only mutations in the X-linked KAL1 and NROB 1 (AHC) genes were identified in IHH patients, studies from our laboratory were instrumental in documenting mutations in the GNRHR gene, the first autosomal gene shown to be causative in IHH. We have also described mutations in the FSHB gene in families with isolated FSH deficiency, and were the first to perform functional studies demonstrating that the FSHB mutants impaired FSH production in vitro. In addition, we presented evidence suggesting that FSH also plays an important role in LH-mediated ovarian androgen production. Although KAL1 and GNRHR comprise about 20% of the mutations described to date, the molecular basis for most IHH patients remains unknown. The long-term goal of our laboratory is to advance our understanding of normal puberty and reproduction by determining the molecular basis of IHH. Our overlying hypothesis is that the genes that regulate gonadotropin production and/or secretion are important in normal puberty and possess mutations in IHH patients. We will test these hypotheses by the following specific aims:
Specific Aim 1 : We hypothesize that chromosomal abnormalities, such as translocations and inversions, identified in IHH patients will provide clues to the location of causative genes etiologic in the pathophysiology of IHH. We will identify the locations of possible candidate genes by determining the prevalence of chromosomal abnormalities in IHH patients. Candidate genes located in the breakpoint regions will then be identified.
Specific Aim 2 : We hypothesize that genes suspected to regulate GnRH and/or gonadotropin function will possess mutations in IHH patients and not controls. We will test candidate genes, determined by their possible effects upon GnRH and gonadotropin function or by their location in chromosomal breakpoints regions, for association and for mutations in patients with IHH vs. fertile controls.
Specific Aim 3 : We hypothesize that gene mutations causing IHH will decrease the expression of the transcript or the amount or function of the encoded protein. We will create the mutant genes, express them in appropriate cell lines in vitro, and determine their effects upon transcription and protein function.
Specific Aim 4 : We hypothesize that patients with more severe mutations (i.e., nonsense mutations and deletions) will have more severe disease than those with less severe mutations. We also hypothesize that the severity of the phenotype may vary for different causative genes. We will perform clinical endocrinologic studies on patients with gene mutations in order to make genotype/phenotype correlations.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Taymans, Susan
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Georgia Health Sciences University
Obstetrics & Gynecology
Schools of Medicine
United States
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Kim, Yeon-Joo; Osborn, Daniel Ps; Lee, Ji-Young et al. (2018) WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. EMBO Rep 19:269-289
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