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