Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (I.R.I.B.H.M.), Faculté de Médecine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Human Mutation (Impact Factor: 5.14). 01/2008; 29(1):91-8. DOI: 10.1002/humu.20604
Source: PubMed


The receptors for follitropin (FSHR), thyrotropin (TSHR), and lutropin/chorionic gonadotropin (LHCGR) are the members of the glycoprotein hormone (GPH) receptors (GPHR) family. They present a bipartite structure with a large extracellular amino-terminal domain (ECD), responsible for high-affinity hormone binding, and a carboxyl-terminal serpentine region, implicated in transduction of the activation signal. Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare genetic condition in which human chorionic gonadotropin (hCG) promiscuously stimulates the FSHR during the first trimester of pregnancy. Surprisingly, germline FSHR mutations responsible for the disease have so far been found only in the transmembrane helices of the serpentine region of the FSHR, outside the hormone binding domain. When tested functionally, all mutants were abnormally sensitive to both hCG and thyrotropin (TSH) while displaying constitutive activity. This loss of ligand specificity was attributed to the lowering of an intramolecular barrier of activation rather than to an increase of binding affinity. Here we report the first germline mutation responsible for sOHSS (c.383C>A, p.Ser128Tyr), located in the ECD of the FSHR. Contrary to the mutations described previously, the p.Ser128Tyr FSHR mutant displayed increase in affinity and sensitivity toward hCG and did not show any constitutive activity, nor promiscuous activation by TSH. Thus, sOHSS can be achieved from different molecular mechanisms involving each functional domains of the FSHR. Based on the structure of the FSHR/FSH complex and site-directed mutagenesis studies, we provide robust molecular models for the GPH/GPHR complexes and we propose a molecular explanation to the binding characteristics of the p.Ser128Tyr mutant.

Download full-text


Available from: Gianluigi Caltabiano,
24 Reads
  • Source
    • "Whatever the underlying etiology for sOHSS, the interaction between glycoprotein hormones and the FSH receptor appears to be a prerequisite for the development of spontaneous OHSS. This explains why symptoms in spontaneous cases of OHSS appear later in pregnancy (8–14 weeks) than in iatrogenic OHSS (3–5 weeks) in which follicular recruitment and enlargement occur during the ovarian stimulation with exogenous FSH [15]. The stimulation of the mutated FSHR occurs at a threshold level of hCG which varies according to the type of mutation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spontaneous ovarian hyperstimulation syndrome is an extremely rare condition that occurs in the absence of ovarian hyperstimulation treatment. It can lead to significant morbidity and mortality, and therefore early diagnosis and supportive treatment are essential. We report an affected mother and her daughter with a previously reported heterozygous activating mutation in the FSHR gene. We performed a literature review with particular regard to pathogenesis, with a view to suggesting a pathophysiological classification system and a diagnostic algorithm to assist in the management of this rare condition.
    European journal of obstetrics, gynecology, and reproductive biology 04/2013; 169(2). DOI:10.1016/j.ejogrb.2013.03.004 · 1.70 Impact Factor
  • Source
    • "Indeed, crystal structures of GTHs, and in particular the crystallization of hFSH/hFSHR–ECD complex (PDB entry 1XWD; Fan and Hendrickson, 2005), have paved the way to increasingly accurate modeling of GTHs and their receptors and to revealing their intermolecular interactions (Caltabiano et al., 2008). Several reports have used molecular modeling to understand the effect of naturally occurring mutations in hCG and hLHR related to syndromes in the human reproductive system (Leung et al., 2006; De Leener et al., 2008). Mutations in GTHRs and structure–function information can be accessed via databases (Van Durme et al., 2006; Kleinau et al., 2007; Kreuchwig et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and their receptors play critical roles in vertebrate reproduction. In order to study intra- and interspecies ligand promiscuity of gonadotropins, COS-7 cells were transiently transfected with one of the gonadotropin receptor genes, FSHR or LHR, and tested for activation by gonadotropins from representative fish orders: Aquilliformes (eel; e), Salmoniformes (trout; tr), and Perciformes (tilapia; ta), and of mammalian origin: porcine (p), bovine (b) and human (h). The study reveals complex relations between the gonadotropin hormones and their receptors. Each gonadotropin activated its own cognate receptor. However, taLHR was also activated by hCG and eLHR was activated by hFSH, hCG, and trFSH. For FSHR, the only cross-reactivity detected was for hFSHR, which was activated by pFSH and bFSH. These findings are of great interest and applicability in the context of activation of various GTHRs by their ligands and by ligands from other vertebrates. Analysis of the three-dimensional models of the structures highlights the importance of residues outside of the currently established hormone-receptor interface region. In addition, the interface residues in taFSHR and the effect of exon duplication, which causes an insert in the LRR domain, are suggested to affect the interaction and binding of taFSH.
    Molecular and Cellular Endocrinology 08/2012; 364(1-2):89-100. DOI:10.1016/j.mce.2012.08.013 · 4.41 Impact Factor
  • Source
    • "Molecular modeling suggested that I545, at the intracellular end of TM3, is part of a tight packing involving residues from TM3 (L460 and T464) and TM6 (I579). Mutations that disrupt the packing either by establishing new interactions (I545T or I545N) or by disrupting the local structure (I545F and I545L) cause constitutive activation, where those that do not are not constitutively active (De Leener et al., 2008). Our previous data showing that L460R mutation can cause constitutive activation is consistent with this hypothesis (Tao et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported in several additional receptors. More recently, loss of constitutive activity was postulated to also cause diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic diseases caused by constitutively activating mutations in GPCRs.
    Pharmacology [?] Therapeutics 09/2008; 120(2):129-48. DOI:10.1016/j.pharmthera.2008.07.005 · 9.72 Impact Factor
Show more