Estrogen Receptor α Inactivation in 2 Sisters: Different Phenotypic Severities for the Same Pathogenic Variant

Author:

Delcour Clémence1ORCID,Khawaja Nahla2,Gonzalez-Duque Sergio3,Lebon Sophie1ORCID,Talbi Abir3,Drira Leila3,Chevenne Didier3,Ajlouni Kamel2ORCID,de Roux Nicolas13ORCID

Affiliation:

1. Université de Paris, INSERM UMR 1141 NeuroDiderot, 75019 Paris, France

2. National Center for Diabetes, Endocrinology and Genetics, Amman 11942, Jordan

3. Biochemistry-Hormonology Laboratory, AP-HP, Robert Debré Hospital, 75019 Paris, France

Abstract

Abstract Context Estrogens play an essential role in reproduction. Their action is mediated by nuclear α and β receptors (ER) and by membrane receptors. Only 3 females and 2 males, from 3 families, with a loss of ERα function have been reported to date. Objective We describe here a new family, in which 2 sisters display endocrine and ovarian defects of different severities despite carrying the same homozygous rare variant of ESR1. Methods A 36-year-old woman from a consanguineous Jordanian family presented with primary amenorrhea and no breast development, with high plasma levels of 17β-estradiol (E2), follicle-stimulating hormone and luteinizing hormone, and enlarged multifollicular ovaries, strongly suggesting estrogen resistance. Her 18-year-old sister did not enter puberty and had moderately high levels of E2, high plasma gonadotropin levels, and normal ovaries. Results Genetic analysis identified a homozygous variant of ESR1 leading to the replacement of a highly conserved glutamic acid with a valine (ERα-E385V). The transient expression of ERα-E385V in HEK293A and MDA-MB231 cells revealed highly impaired ERE-dependent transcriptional activation by E2. The analysis of the KISS1 promoter activity revealed that the E385V substitution induced a ligand independent activation of ERα. Immunofluorescence analysis showed that less ERα-E385V than ERα-WT was translocated into the nucleus in the presence of E2. Conclusion These 2 new cases are remarkable given the difference in the severity of their ovarian and hormonal phenotypes. This phenotypic discrepancy may be due to a mechanism partially compensating for the ERα loss of function.

Funder

ENDORE

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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