Hypogonadism; GnRH deficiency; Human Genetics; Fibroblast Growth Factor Signaling; Bone Morphogenetic Protein 4 signaling
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Patients with gonadotropin-releasing hormone (GnRH) deficiency present a unique investigative opportunity to elucidate the genes and mechanisms controlling human reproduction. Our group and others have discovered that no fewer than 13% of patients with GnRH deficiency harbor germline mutations in fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor 8 (FGF8), and have established a critical role of this pathway in the ontogeny of GnRH neurons. This project will use a multidisciplinary strategy that combines human genetics and clinical pathophysiology with structural and molecular biology and bioinformatics, to achieve the following goals: 1) to identify additional genes in the FGF8 pathway that are mutated in GnRH-deficient patients; 2) to discover novel genes/pathways underlying human GnRH deficiency; and 3) to investigate to what extent the genetic architecture of human GnRH deficiency is sufficiently explained by interacting mutations in the known and novel disease genes. Addressing these issues will enhance our understanding of the neuroendocrine control of reproduction, and will have important implications for the genetic counseling of GnRH-deficient patients and their families. Moreover, identifying novel disease genes may provide new avenues for the treatment of human infertility and sex steroid-related diseases which are either related to abnormal activity of the hypothalamic-pituitary-gonadal axis, such as polycystic ovarian syndrome and hypothalamic amenorrhea, or can be treated by pharmacological manipulation of the axis, such as breast and prostate cancer.Aim 1: To expand the genetic network of FGF8/FGFR1 signaling implicated in GnRH ontogeny in the human.Hypothesis 1: Patients with GnRH deficiency and associated non-reproductive phenotypes harbor mutations in members of the FGF8 genetic network (FGF8 synexpression group), which includes FGF8-subfamily ligands (FGF17), inhibitors (similar expression as FGF, SEF), and enhancers (fibronectin-like domain-containing leucine-rich transmembrane protein-3, FLRT3).Hypothesis 2: GnRH deficiency-associated mutations in members of the FGF8 genetic network lead to decreased FGFR1 signaling.Aim 2: To discover novel pathways involved in GnRH ontogeny in humans.Hypothesis 3: GnRH-deficient patients harbor mutations in bone morphogenetic protein 4 (BMP4) that impair SMAD signaling. Aim 3: To further define the oligogenic architecture of congenital GnRH deficiency in humans Hypothesis 4: A significant proportion of GnRH-deficient patients have oligogenic disease, each harboring multiple mutations in genes that lie within the same pathway and/or across different pathways.Hypothesis 5: The segregation patterns of oligogenic mutations correlate with the variable expressivity of reproductive phenotypes among family members of GnRH-deficient patients.