Genetic analyses of humans with GnRH deficiency (Kallmann's Syndrome [KS] and normosmic idiopathic hypogonadotropic hypogonadism [nIHH]) have provided unique insights into the genes controlling sexual maturation (KAL1, GNRHR, FGFR1, and GPR54). The discovery that FGFR1 mutations causes KS demonstrated a critical role of FGF signaling in olfactory bulb morphogenesis and GnRH neuron migration. However, one important and unsolved issue in GnRH neuronal development is the identification of the physiologic FGF(s) for FGFR1 in GnRH ontogeny. Furthermore, FGF signaling controls a plethora of critical biologic processes throughout development, including cell fate, cell migration, and cell survival, but the mechanism by which such widespread FGF signaling is tightly regulated and specialized remains unknown. The coordinate spatial and temporal expression of several genes within the FGF signaling pathway -FGF8 syn- expression group- suggests an evolutionarily conserved genetic network, including inhibitors and enhancers of FGF8 signaling. We hypothesize that the FGF8 syn-expression group modulates FGF signaling during GnRH neuron development and has a key role in human reproduction. Therefore, the aims of this proposal are to: 1) Identify key components of the FGF pathway critical for GnRH ontology 2) Perform genotype-phenotype correlations for mutations in the FGF pathways causing IHH, and 3) Study mutant FGF protein using crystallography and molecular and cell biology techniques.

Public Health Relevance

The information generated from the proposed studies will increase our understanding of the genetics of sexual maturation. It will also provide valuable genotype-phenotype information that will have clinical relevance for both children and adults in terms of diagnosis and understanding of the mechanism of pubertal disorders as well as initiating new opportunities for genetic counseling. Further, these genetic studies will provide critical pathophysiologic insights into the role of FGF8 signaling pathway in human reproduction. Such understanding is required to design future targeted therapies. In general terms, the focus of this project is to explore the genetic causes of reproductive conditions and will provide a foundation for understanding, diagnosing, and genetic counseling of these disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD056264-05
Application #
8326966
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$220,918
Indirect Cost
$13,119
Name
Centre Hospitalier Universitaire Vaudois
Department
Type
DUNS #
481700292
City
Lausanne
State
Country
Switzerland
Zip Code
1011
Villanueva, Carine; Jacobson-Dickman, Elka; Xu, Cheng et al. (2015) Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations. Genet Med 17:651-9
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
Goetz, Regina; Ohnishi, Mutsuko; Ding, Xunshan et al. (2012) Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol Cell Biol 32:1944-54
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
Tornberg, Janne; Sykiotis, Gerasimos P; Keefe, Kimberly et al. (2011) Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A 108:11524-9
Caronia, Lisa M; Martin, Cecilia; Welt, Corrine K et al. (2011) A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 364:215-25
Shaw, Natalie D; Seminara, Stephanie B; Welt, Corrine K et al. (2011) Expanding the phenotype and genotype of female GnRH deficiency. J Clin Endocrinol Metab 96:E566-76
Sykiotis, Gerasimos P; Hoang, Xuan-Huong; Avbelj, Magdalena et al. (2010) Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 95:3019-27

Showing the most recent 10 out of 13 publications