Estrogen Receptor alpha 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 ER 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 ESR1 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.