Project

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The Neuroendocrine Control of Human Reproduction

Applicant Pitteloud Nelly
Number 135648
Funding scheme Project funding (Div. I-III)
Research institution Division d'endocrinologie, diabétologie et du métabolisme Département de médecine interne - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Endocrinology
Start/End 01.04.2011 - 31.03.2014
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Endocrinology
Genetics

Keywords (5)

Hypogonadism; GnRH deficiency; Human Genetics; Fibroblast Growth Factor Signaling; Bone Morphogenetic Protein 4 signaling

Lay Summary (English)

Lead
Lay summary

Gonadotropin releasing hormone (GnRH) is the pilot light of reproduction.  As such, human GnRH) deficiency is a unique human disease model to provide into the genetics of puberty and reproduction.  Emerging researhc over the past several years has identified the key role of fibroblast growth factor (FGF) signaling in GnRH neuron ontogeny and the control of human reproduction and the growing notion of oligogenicity or how several genes interact to cause disease.   Indeed, as we learn more about FGF signaling and the oligogenic architecture of GnRH deficiency, it is becoming clearer that the FGF signaling pathway plays a critical role a number of complex biologic processes related to human reproduction. 

Broadly, the aims of this project is to identify genes within the FGF signaling pathway (FGF8 syn-expression group), explore novel pathways underlying GnRH deficiency, and to further elucidate the oligogenic architecture of these disorders.  The information generated from the proposed studies will increase and deepen our understanding of the genetics of sexual maturation and reproduction and thus will help enhance the diagnosis, treatment, and genetic counseling of patients and families with these disorders.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).
Koika v et. al. (2013), Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH)., in Gene, 516(1), 146-151.
Prioritizing genetic testing in Kallmann syndrome (KS): The utility of reproductive and non-reproductive clinical features
Costa Barbosa et al (2013), Prioritizing genetic testing in Kallmann syndrome (KS): The utility of reproductive and non-reproductive clinical features, in J Clin Endocrinol Metab, 98(5), E943-E953.
Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia.
Raivio T et. al. (2012), Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia., in J Clin Endocrinol Metab, 97(4), E694-E699.
Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands
Goetz R et. al. (2012), Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands, in Mol Cell Biol, 32, 1944-1954.
A genetic basis for hypothalamic amenorrhea
Caronia LM et. al (2011), A genetic basis for hypothalamic amenorrhea, in N Engl J Med, 364, 215-225.
Expanding the phenotype and genotype of female GnRH deficiency.
Shaw ND et. al. (2011), Expanding the phenotype and genotype of female GnRH deficiency., in J Clin Endocrinol Metab, 96(3), E566-E576.
Genetic basis and variable phenotypic expression of Kallmann syndrome: Towards a unifying theory
Mitchell AL et. al. (2011), Genetic basis and variable phenotypic expression of Kallmann syndrome: Towards a unifying theory, in Trends Endocrinol Metab., 22(7), 249-258.
Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patietns with idiopathic hypogonadotropic hypogonadism
Torberg J et. al (2011), Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patietns with idiopathic hypogonadotropic hypogonadism, in Proc Natl Acad Sci USA, 108, 11524-11529.
Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.
McCabe MJ et. al. (2011), Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction., in J Clin Endocrinol Metab, 96, E1709-E1718.
Role of Fibroblast Growth Factor (FGF) Signaling in the Neuroendocrine Contorl of Human Reproduction
Miraoui et al (2011), Role of Fibroblast Growth Factor (FGF) Signaling in the Neuroendocrine Contorl of Human Reproduction, in Mol Cell Endocrinol, 346(1-2), 37-43.
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism
Miraoui Hichem et. al., Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism, in American Journal of Human Genetics, 92(5), 725-743.

Collaboration

Group / person Country
Types of collaboration
Prof. Schönle & Dr. Lang-Muritano, Endocrinology & Diabetes, Zurich University Childrens Hospital Switzerland (Europe)
- Research Infrastructure
Prof. Luca Persani, Department of Endocrinology, University of Milan Italy (Europe)
- Research Infrastructure
Prof. Pei Tsai, Center for Neuroscience, University of Colorado United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. William Crowley Jr., Reproductive Endocrine Unit, Massachusetts General Hospital United States of America (North America)
- Publication
Prof. Moosa Mohammadi, Department of Pharmacology, New York University School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Neoklis Georgopoulos, Department of Endocrinology, University of Patras Greece (Europe)
- Publication
Dr. Richard Quinton, Department of Endocrinology, Newcastle-upon-Tyne University Great Britain and Northern Ireland (Europe)
- Publication
Dr. Taneli Raivio, MD, PhD, Department of Pediatrics, Helsinki University Cental Hospital Finland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Yiming Li, Department of Medicine & Endocrinology, Fudan University China (Asia)
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Society of Human Genetics Annual Meeting Poster Mutations in the BMP genetic network in patients with congenital GnRH deficiency 01.10.2013 Boston, United States of America Cassatella Daniele; Xu Cheng; Miraoui Hichem; Pitteloud Nelly;
9th Joint Meeting of Paediatric Endocrinology Poster Prepubertal diagnosis of CHH by whole-exome sequencing in a neonate with microphallus and cryptorchidism 01.09.2013 Milan, Italy Xu Cheng; Pitteloud Nelly;
94th Annual Meeting of the Endocrine Society Poster Interactome-Based Affiliation Scoring (IBAS) is a Novel Bioinformatic Tool to Identify and Prioritize Canditate Genes: Validation study in Congenital Hypogonadotropic Hypogonadism 01.06.2013 San Francisco, CA, United States of America Pitteloud Nelly; Miraoui Hichem;
University of Lausanne Faculty of Biology and Medicine Research Day- "The World of Omics" Poster Identifying new disease-associated genes in Kallmann syndrome using whole-exome sequencing 01.06.2012 Lausanne, Switzerland Pitteloud Nelly; Cassatella Daniele;
Gordon Research Conference "Fibroblast Growth Factors in Development & Disease" Poster Role of FRS2/FRS3 in GnRH neuron ontogeny 01.05.2012 Les Diablerets, Switzerland Pitteloud Nelly; Cassatella Daniele;
Gordon Research Conference "Fibroblast Growth Factors in Development & Disease Poster Role of FRS2/FRS3 in GnRH neuron ontogeny 01.05.2012 Les Diablerets, Switzerland Pitteloud Nelly; Cassatella Daniele;
93rd Annual Meeting of the Endocrine Society Talk given at a conference Gain-of-function mutations in FGFR1 in human GnRH deficiency 01.06.2011 Boston, United States of America Pitteloud Nelly; Miraoui Hichem;
93rd Annual Meeting of the Endocrine Society Poster Mutations in the FGF8 genetic network underlie a large proportion of isolated human GnRH deficiency 01.06.2011 Boston, United States of America Miraoui Hichem; Pitteloud Nelly;


Awards

Title Year
Best Poster Award: "Identifying new disease-associated genes in Kallmann syndrome using whole-exome sequencing". D. Cassatella, J Liang, A Dwyer, JP Rey, VH Hughes, R Quinton, P Bouloux, M Lang-Muritano, Y Sidis, N Pitteloud. University of Lausanne Faculty of Biology and Medicine Research Day “The World of Omics”. Lausanne, Switzerland - June 2012. 2012

Associated projects

Number Title Start Funding scheme
153328 The Neuroendocrine Control of Human Reproduction 01.04.2014 Project funding (Div. I-III)
173260 The Neuroendocrine Control of Human Reproduction 01.04.2017 Project funding (Div. I-III)
148908 Exploring the molecular basis and phenotypic spectrum of reproductive disorders in South Africa 01.01.2014 Bilateral programmes
141960 FGF21 is a link between reproduction and energy balance 01.12.2012 Sinergia

Abstract

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.
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