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Early-onset complete ovarian failure and lack of puberty in a woman with mutated estrogen receptor β (esr2)

  • Lang-Muritano, Mariarosaria Division of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, - Switzerland
  • Sproll, Patrick Division of Endocrinology, University of Fribourg, Switzerland
  • Wyss, Sascha Division of Endocrinology, University of Fribourg, Switzerland
  • Kolly, Anne Division of Endocrinology, University of Fribourg, Switzerland
  • Hürlimann, Renate Division of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich,
  • Konrad, Daniel Division of Pediatric Endocrinology and Diabetology, University Children’s Hospital, Zurich, - Switzerland
  • Lauber-Biason, Anna Division of Endocrinology, University of Fribourg, Switzerland
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    01.10.2018
Published in:
  • The Journal of Clinical Endocrinology & Metabolism. - 2018, vol. 103, no. 10, p. 3748–3756
English Estrogen resistance due to mutations in the estrogen receptor α gene (ESR1) has been described in men and women and is characterized by osteoporosis, delayed bone age and continuous growth in adulthood, and delayed puberty and multiple ovarian cysts in women. Although mutations in the estrogen receptor β gene ESR2 were found in 46, XY patients with differences of sex development, no genetic variants of ESR2 were linked to gonadal defects in women.Settings and Patient: Here we describe a 16-year-old female patient who came to our tertiary care hospital with complete lack of estrogen action, as demonstrated by absent breast development, primary amenorrhea, and osteoporosis, resembling patients with ESR1 mutation. However, her gonads were clearly abnormal (streak), a finding not observed in ESR1- deficient patients.Design: To gain insights into the molecular consequences of the ESR2 defect, whole exome sequencing and extensive functional transactivation studies in ovarian, bone, and breast cells were conducted, with or without the natural activator of estrogen receptors, 17β-estradiol.Results: We identified a loss-of-function heterozygous mutation of a highly conserved residue in ESR2 that disrupts estradiol- dependent signaling and has a dominant negative effect, most likely due to failure to interact with its coactivator, nuclear coactivator 1.Conclusions: This is a report of a loss-of-function mutation in the estrogen receptor β in a young woman with complete ovarian failure, suggesting that ESR2 is necessary for human ovarian determination and/or maintenance and that ESR1 is not sufficient to sustain ovarian function in humans.
Faculty
Faculté des sciences et de médecine
Department
Médecine 3ème année
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/307282
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