ESPE Abstracts (2019) 92 RFC15.6

Absence of Puberty and Estrogen Resistance by Estrogen Alpha Receptor Inactivation in Two Sisters: A Mutation for Variable Phenotypic Severity

Clémence Delcour1, Nahla Khawaja2, Hedi Mammeri3, Leila Drira4, Didier Chevenne5, Kamel Ajlouni2, Nicolas De Roux1,4

1Université de Paris, INSERM U1141, Paris, France. 2National Center for Diabetes, Endocrinology and Genetics/ The University of Jordan, Amman, Jordan. 3Université de Paris, INSERM IAME UMR 1137, paris, France. 4Laboratoire Biochimie-Hormonologie, Hôpital Robert Debré, Paris, France. 5Laboratoire Biochimie-Hormonologie, Hôpital Robert Debré, paris, France

Introduction: Estrogens play an essential role in reproduction and their peripheral action is mediated via nuclear alfa and beta receptors (ER) as well as membrane receptors. To date, only 3 females and 2 males from 3 families with a loss of function of ERa have been reported. The phenotype in these families was strongly suggestive of an estrogen resistance with an absence of a complete puberty, a delay in epiphyseal maturation with high estradiol levels and elevated gonadotropin levels.

Goal: The objective of this study was to describe a new family in which 2 sisters displayed different levels of endocrine and ovarian defects although they carried the same homozygous rare variant in the ERa-encoding ESR1 gene.

Materials and Methods: A 36-year-old woman with a primary amenorrhea and no breast development, had elevated 17β-estradiol (1497 pg/ml), high FSH (57 IU/L) and LH (21 IU/L) plasma levels, and enlarged multifollicular ovaries (11 and 17 ml). Her 18-year-old sister did not enter puberty and had moderate increases in 17β-estradiol (204 pg/ml) with high FSH (29 IU/L) and LH (22 IU/L) plasma levels and ovaries of normal size. The parents are consanguineous.

Results: In both cases, genetic analysis identified a homozygous variant of ESR1 (c.1154A>T) leading to the substitution of the highly conserved glutamic acid at position 385 by a valine (p.Glu385Val). Both parents as well as an unaffected sister were heterozygous for the variant. The Glu385 is located in the ligand binding domain and the in-silico analysis predicted a deleterious effect on the protein function. Modeling study of the ERa-E385V variant showed a slight displacement of the H-12 helix, which plays a crucial role in signal transmission, suggesting that the Glu385Val replacement might preclude the activation of the receptor.

A functional analysis was performed by transient expression of WT-ERa or Glu385Val-ERa in HEK293A cells. Glu385Val-ERa transfected cells showed a strong decrease in transcriptional activation by 17β-estradiol of a reporter gene controlled by a standard estradiol-responsive-element as well as a milder inhibition of the KISS1 promoter when compared to WT-ERa. Immunofluorescence analysis showed lower nuclear translocation of E385V-ERa in the presence of 17β-estradiol as compared to WT-ERα.

Conclusion: These two new cases are remarkable as they are sisters and they display a different level of severity of the ovarian and hormonal phenotypes. This phenotypic discrepancy could be attributable to a mechanism that could partially compensate the ERa inactivation.

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