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

Context: Estrogens play an essential role in reproduction. Their action is mediated by nuclear [alpha] and [beta] receptors (ER) and by membrane receptors. Only 3 females and 2 males, from 3 families, with a loss of EF[alpha] function have been reported to date. Objective: We describe here a new fam...

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Published in:The journal of clinical endocrinology and metabolism 2022-06, Vol.107 (6), p.e2553
Main Authors: Delcour, Clemence, Khawaja, Nahla, Gonzalez-Duque, Sergio, Lebon, Sophie, Talbi, Abir, Drira, Leila, Chevenne, Didier, Ajlouni, Kamel, de Roux, Nicolas
Format: Article
Language:English
Subjects:
Amino acids
Estradiol
Family
Follicle-stimulating hormone
Glutamate
Glycoproteins
Luteinizing hormone
Phenols
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Summary:Context: Estrogens play an essential role in reproduction. Their action is mediated by nuclear [alpha] and [beta] receptors (ER) and by membrane receptors. Only 3 females and 2 males, from 3 families, with a loss of EF[alpha] 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 17[beta]-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 ESFt1 leading to the replacement of a highly conserved glutamic acid with a valine (ER[alpha]-E385V). The transient expression of ER[alpha]-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 ER[alpha]. Immunofluorescence analysis showed that less ER[alpha]-E385V than ER[alpha]-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 ER[alpha] loss of function. KeyWords: estrogen receptor, puberty, hypergonadotropic hypogonadism, kisspeptin
ISSN:0021-972X
DOI:10.1210/clinem/dgac065