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The Neuroendocrine Control of Human Reproduction

English title The Neuroendocrine Control of Human Reproduction
Applicant Pitteloud Nelly
Number 153328
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 01.04.2014 - 31.03.2017
Approved amount 756'000.00
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All Disciplines (3)

Discipline
Endocrinology
Clinical Endocrinology
Genetics

Keywords (5)

Pubertal disorders; Human Genetics; Development; Hypogonadism; GnRH deficiency

Lay Summary (French)

Lead
Ce projet utilise une approche multi-disciplinaire et des nouvelles technologies à approfondir notre compréhension du contrôle génétique de la reproduction et de la puberté chez les humains.
Lay summary

Nous utilisons une maladie rare, hypogonadisme hypogonadotrophique congénital (CHH), afin d'avoir un mieux compréhension de la puberté et de la reproduction chez l'homme. L'objectif de la présente étude est d'utiliser les caractéristiques cliniques de CHH de développer des approches plus efficace pour le diagnostic afin d'atténuer certains des problèmes psychologiques associés à cette condition. De plus, nous utilisons les nouvelles technologies génétiques pour découvrir les gènes qui contrôlent la puberté et la reproduction. Ces découvertes permettront d'améliorer nos approches diagnostiques, le conseil des patients et des familles avec ces conditions, et peuvent identifier des traitements pour infertilité et les cancers qui sont sensibles des stéroïdes sexuel comme le cancer de le sein et prostate. 

Direct link to Lay Summary Last update: 26.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism
Xu C., Lang-Muritano M., Phan-Hug F., Dwyer A.A., Sykiotis G.P., Cassatella D., Acierno J., Mohammadi M., Pitteloud N. (2017), Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism, in Clinical Genetics, 1399.
β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue
Somm Emmanuel, Henry Hugues, Bruce Stephen J., Aeby Sébastien, Rosikiewicz Marta, Sykiotis Gerasimos P., Asrih Mohammed, Jornayvaz François R., Denechaud Pierre Damien, Albrecht Urs, Mohammadi Moosa, Dwyer Andrew, Acierno James S., Schoonjans Kristina, Fajas Lluis, Greub Gilbert, Pitteloud Nelly (2017), β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue, in JCI Insight, 2(8), e91809.
Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations
Villanueva C, Jacobson-Dickman E, Xu C, ManouvrierS, DwyerA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel J, Phan-Hug F, Hauschild M, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, Pitteloud N, Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations, in Genetics in Medicine, 2014 Nov 13 ([Epub ahea).

Collaboration

Group / person Country
Types of collaboration
Tarja Kinnunen PhD / University of Huddersfield, Department of Biology Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Zoltan Kutalik, PhD / University of Lausanne & Institute of Social & Preventive Medicine Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ken Ong, MD / MRC Epidemiology Unit, Institute of Metabolic Science Addenbrooke's Hospital Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ioannis Xenarios, PhD / University of Lausanne & Swiss Institute of Bioinformatics Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Moosa Mohammadi, PhD / 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
Paolo Giacobini, PhD / INSERM Unit 837 Lille France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Nicholas Katsanis, PhD / Center for Human Disease Modeling, Duke University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Assemblee Annuelle de la Societe Suisse d’Endocrinologie et de Diabetologie Talk given at a conference β-Klotho deficiency protects against obesity: a crosstalk between liver, microbiota and brown adipose tissue 18.11.2016 Bern, Switzerland Somm Emmanuel;
4th NICe Workshop, The Italian Network of Central hypogonadism Talk given at a conference Insights into the Pathogenesis of Central Hypogonadism in Humans 30.09.2016 Genova, Italy Pitteloud Nelly;
LIMNA symposium "Muscle stem cells, Metabolism and Ageing" Talk given at a conference β-Klotho deficiency protects against obesity: a crosstalk between liver, microbiota and brown adipose tissue 27.09.2016 Lausanne, Switzerland Somm Emmanuel;
International Congress of Endocrinology (ICE) and the China Society of Endocrinology (CSE) Talk given at a conference FGFR mutations in congenital hypogonadotropic hypogonadism 31.08.2016 Beijing, China Pitteloud Nelly;
4th Scientific Meeting & Training School - COST Action BM1105 Talk given at a conference Illness perceptions and quality of life in women with congenital hypogonadotropic hypogonadism (CHH) 03.06.2016 Budapest, Hungary Pitteloud Nelly;
4th Scientific Meeting & Training School - COST Action BM1105 Talk given at a conference Mutations in BMP4 gene network are associated with Kallmann syndrome 03.06.2016 Budapest, Hungary Pitteloud Nelly;
4th Scientific Meeting & Training School - COST Action BM1105 Talk given at a conference A Novel Role for Anti-Müllerian Hormone in the Development of the GnRH System 06.03.2016 Budapest, Hungary Pitteloud Nelly;
4th Scientific Meeting & Training School - COST Action BM1105 Talk given at a conference Phenotype-genotype analysis in patients with GnRH deficiency in a single center 06.03.2016 Budapest, Hungary Pitteloud Nelly;
4th Scientific Meeting & Training School - COST Action BM1105 Talk given at a conference Next generation sequencing to discover novel genes in congenital hypogonadotropic hypogonadism 06.03.2016 Budapest, Hungary Pitteloud Nelly;
Royal Society of Medicine - Puberty: the hinterland between childhood and adulthood Talk given at a conference GnRH: an overview of its critical role in puberty and reproductive development 27.01.2016 London, Great Britain and Northern Ireland Pitteloud Nelly;
2nd Joint Scientific Meeting and Training School - COST Action BM1105 Talk given at a conference Systematic investigation of oligogenicity in a large cohort of CHH patients via exome sequencing 27.04.2015 Prato, Italy Pitteloud Nelly;
Annual meeting of the Swiss Society of Endocrinology and Diabetes Poster Exome sequencing identifies Neuron-Derived Neutrophic Factor (NDNF) as a candidate gene for Kallmann Syndrome 28.11.2014 Switzerland, Switzerland Pitteloud Nelly;
The endocrine society’s 96th annual meeting Talk given at a conference KLB, encoding the co-receptor for FGF21, is mutated in congenital GnRH deficiency 15.06.2014 Chicago, United States of America Somm Emmanuel; Pitteloud Nelly;


Associated projects

Number Title Start Funding scheme
173260 The Neuroendocrine Control of Human Reproduction 01.04.2017 Project funding (Div. I-III)
135648 The Neuroendocrine Control of Human Reproduction 01.04.2011 Project funding (Div. I-III)
141960 FGF21 is a link between reproduction and energy balance 01.12.2012 Sinergia
173260 The Neuroendocrine Control of Human Reproduction 01.04.2017 Project funding (Div. I-III)

Abstract

Our research focuses on genetic investigations of patients with deficiency in the hypothalamic gonadotropin-releasing hormone (GnRH), which is the master regulator of the mammalian reproductive axis. We employ a multidisciplinary and translational approach: (i) By identifying genes and mutations underlying GnRH deficiency (congenital hypogonadotropic hypogonadism, CHH), we facilitate the molecular diagnosis and genetic counseling of patients and their families. (ii) The mutated genes mark the central pathways that are important in vivo for human reproduction, opening new fields for basic investigations. (iii) By elucidating the complex genetic architecture of CHH, we establish new paradigms applicable to other rare diseases.Over the last three years, we transferred our lab from Boston to Lausanne, and accomplished the following:(i) Discovered new genes for CHH among candidates in the FGF signaling network and the BMP pathway. (ii) Validated a new bioinformatics tool based on proteome-wide interactions to prioritize candidates for genetic diseases. (iii) Further supported an oligogenic model for the architecture of CHH, by showing that it explains a substantial proportion of CHH cases. (iv) Described new clinical syndromes encompassing CHH, and began to elucidate the phenotypic and underlying genetic overlap. (v) Demonstrated that mutations in CHH genes predispose women to hypothalamic amenorrhea, a common and reversible form of GnRH deficiency. (vi) Organized a Europe-wide network (COST Action) of clinical and basic researchers focused on GnRH biology. (vii) Established an authorized molecular laboratory for the genetic diagnosis of rare endocrine diseases. In the present project, we propose to advance this translational line of investigation by incorporating the following new tools and concepts: (i) Next-generation sequencing technologies combined with bioinformatics and statistical approaches to account for the genetic complexity of CHH. (ii) Expansion of the CHH-associated sub-phenotypes and overlapping genetic syndromes to guide personalized gene identification. (iii) Use of new genomics resources to map pathway important for GnRH biology, and new model organisms (C.elegans and zebrafish) to assess the pathogenicity of CHH-associated mutations in vivo. (iv) Bridge the genetic divide between rare diseases and common traits by searching for CHH-causing mutations in genes marked by common variants associated with variation in pubertal timing.The specific aims of our proposal are as follows:Aim 1: To capitalize on the phenotypic complexity of patients with congenital hypogonadotropic hypogonadism (CHH) in order to facilitate individualized genetic diagnosis.Aim 2: To discover new genes for CHH by prioritizing whole-exome sequencing data and functional genomics.Aim 3: To discover novel genes for CHH among those associated with pubertal timing in genome-wide association studies (GWAS).
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