Ovarian Hyperstimulation Syndrome Due to a Mutation in the Follicle-Stimulating Hormone Receptor

Smits, Guillaume; Olatunbosun, Olufemi A.; Delbaere, Anne; Pierson, R.A.; Vassart, Gilbert; Costagliola, Sabine

doi:10.1056/nejmoa030064

Cited by 253 publications

(167 citation statements)

References 23 publications

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“…Of note, whereas FSHr constitutively active mutations are located in the TMD (Fig. 4a) and are associated with promiscuous hormone selectivity 5,18,19,39 , the residues we tested in constitutive LH/CGrs are located in the ECD or extracellular loops (ECL) (Fig. 4c).…”

Section: Activity-caused Cooperativity Reduction Is a General Signaturementioning

confidence: 99%

“…The existence of a reciprocal, 'bottom-up' , communication between the TMD and the ECD is evident in the mutant FSHr present in patients with ovarian hyperstimulation syndrome 19,40,56 . The majority of these mutants show various degree of constitutive activity secondary to amino-acid substitutions in the TMD and show promiscuous activation by both chorionic gonadotropin and TSH 39 .…”

Section: Di(oligo)merization Ofmentioning

confidence: 99%

“…The majority of these mutants show various degree of constitutive activity secondary to amino-acid substitutions in the TMD and show promiscuous activation by both chorionic gonadotropin and TSH 39 . In addition, these constitutively active hFSHr can be activated by hCG unlike the WT hFSHr 19,40,56 . This loss of selectivity of the FSHr resulting from increased basal activity is a property not shared by either TSHr 39 or LH/CGr 57 .…”

Section: Di(oligo)merization Ofmentioning

confidence: 99%

“…Interestingly, although most of these are located in the rhodopsin-like TMD, in the case of the FSHr, they allosterically impact on hormone specificity 18,19 . The mechanisms or structures that regulate the reciprocal interaction between the ECD and TMD are unclear at the present time.…”

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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

et al. 2012

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Glycoprotein hormone receptors show strong negative cooperativity. As a consequence, at physiological hormone concentrations, a single agonist binds to a receptor dimer. Here we present evidence that constitutively active receptors lose cooperative allosteric regulation in direct relation with their basal activity. The most constitutive mutants lost nearly all cooperativity and showed an increase of initial tracer binding, reflecting the ability of each protomer to bind with equal affinity. Allosteric interaction between the protomers takes place at the transmembrane domain. The allosteric message resulting from hormone binding to the ectodomain of one protomer travels 'downward' to its transmembrane domain, before affecting the transmembrane domain of the other protomer. This results in transmission of an 'upward' message lowering the binding affinity of the ectodomain of the second protomer. our results demonstrate a direct relation between the conformational changes associated with activation of the transmembrane domain and the allosteric behaviour of glycoprotein hormone receptors dimers.

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Section: Activity-caused Cooperativity Reduction Is a General Signaturementioning

confidence: 99%

Section: Di(oligo)merization Ofmentioning

confidence: 99%

Section: Di(oligo)merization Ofmentioning

confidence: 99%

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confidence: 99%

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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

et al. 2012

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“…Persistent stimulation of the FSH receptor during pregnancy resulted in excessive follicular recruitment and subsequent ovarian hyperstimulation. [5][6][7] One case of spontaneous OHSS in pregnancy was attributed to a mutation in the hCG/LH receptor gene, which led to an exaggerated response to normal hCG levels. 8 Our patient's hCG level was markedly elevated at 430 525 IU l À1 .…”

Section: Discussionmentioning

confidence: 99%

Ovarian hyperstimulation syndrome associated with fetal trisomy 21

et al. 2009

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We report a case of ovarian hyperstimulation syndrome associated with fetal trisomy 21. A primigravida presented at 17 1/7 weeks of gestation with abdominal pain because of enlarged ovaries. Multiple fetal abnormalities were seen on pregnancy ultrasound. Fetal trisomy 21 was diagnosed by amniocentesis. The patient's human chorionic gonadotropin level was markedly elevated, as often occurs with fetal trisomy 21, and was likely associated with the ovarian hyperstimulation. Ovarian hyperstimulation syndrome associated with fetal aneuploidy has not been previously described. Journal of Perinatology (2009) 29, 388-390; doi:10.1038/jp.2008 Keywords: aneuploidy; trisomy 21; ovarian hyperstimulation CaseThe ovarian hyperstimulation syndrome (OHSS) refers to a combination of ovarian enlargement because of multiple ovarian cysts and an acute fluid shift out of the intravascular space. Most cases of OHSS are associated with the use of exogenously administered gonadotropins and occasionally clomiphene citrate. We discuss a case of mild OHSS resulting from a singleton gestation conceived after spontaneous ovulation. The pregnancy was complicated by fetal trisomy 21; serum human chorionic gonadotropin (hCG) levels were presumably associated with the OHSS.A 35-year-old Asian primigravida who conceived spontaneously presented to the emergency room at 17 1/7 weeks of gestation with abdominal pain of 2 days' duration. She denied fevers, nausea, vomiting, diarrhea or other complaints. Her prenatal course had been unremarkable until that point. She had not undergone serum screening for her advanced maternal age status. She had no notable medical, surgical or gynecologic history. She used no medications and had no drug allergies. She did not smoke, drink alcohol or use drugs. Vital signs were stable. On physical exam, the abdomen was tender in both lower quadrants, but without rebound or guarding. Bowel sounds were normal. On pelvic exam, the cervix was closed and nontender. No discharge or bleeding were appreciated.On laboratory testing, complete blood count and electrolytes were within normal limits. hCG level was 430 525 IU l À1 . Pelvic ultrasound showed enlarged maternal ovaries. The right ovary measured 6.2 Â 4.9 Â 4.6 cm and contained multiple cysts, the largest measuring 2.8 cm. The left ovary measured 3.8 Â 4.5 Â 3.5 cm, also with multiple cysts, the largest measuring 1.8 cm. Pregnancy ultrasound showed fetal biometry consistent with 17 1/7 weeks of gestation. A 1.6 cm cystic hygroma was seen, along with hydrops. Scalp edema and ascites were visible. The amniotic fluid volume was normal. The patient was discharged home from the emergency room with prescriptions for pain medication.The next day, the patient presented for counseling regarding the fetal ultrasound. She elected to undergo amniocentesis; the karyotype indicated fetal trisomy 21. Pregnancy options were discussed; the patient opted for expectant management. At 18 weeks, ultrasound showed a fetal pericardial effusion. At 19 weeks, severe oligohydramnios developed. ...

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

et al. 2008

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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.

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Ovarian Hyperstimulation Syndrome Due to a Mutation in the Follicle-Stimulating Hormone Receptor

Cited by 253 publications

References 23 publications

Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

Ovarian hyperstimulation syndrome associated with fetal trisomy 21

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

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