In:
The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 6 ( 2022-05-17), p. e2553-e2562
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
0021-972X
,
1945-7197
DOI:
10.1210/clinem/dgac065
Sprache:
Englisch
Verlag:
The Endocrine Society
Publikationsdatum:
2022
ZDB Id:
2026217-6
