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Case Reports
. 2017 Jan 1;102(1):93-99.
doi: 10.1210/jc.2016-2749.

Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation

Valérie Bernard  1 , Sakina Kherra  2 , Bruno Francou  1   3 , Jérôme Fagart  1 , Say Viengchareun  1 , Jérôme Guéchot  4 , Asmahane Ladjouze  5 , Anne Guiochon-Mantel  1   3 , Kenneth S Korach  6 , Nadine Binart  1 , Marc Lombès  1   7 , Sophie Christin-Maitre  8   9
Affiliations
Case Reports

Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation

Valérie Bernard et al. J Clin Endocrinol Metab. .

Abstract

Context: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) α and β, encoded by ESR1 and ESR2 genes, respectively.

Objective: The study's aim was to describe a family in which 3 members presented with estrogen insensitivity.

Design and setting: Clinical evaluation and genetic and mutational analysis were performed in an academic medical center.

Patients and interventions: An ESR1 mutation was identified in 2 sisters and 1 brother, originating from a consanguineous Algerian family, who did not enter puberty and presented with delayed bone maturation consistent with estrogen insensitivity. The 2 sisters had enlarged multicystic ovaries. Hormonal evaluation as well as genetic and mutational analysis were performed.

Results: Hormonal evaluation revealed extremely high plasma 17β-estradiol (>50-fold normal range) associated with elevated gonadotropin levels (greater than threefold normal range), highly suggestive of estrogen resistance. The 3 affected patients carried a homozygous mutation of a highly conserved arginine 394 for which histidine was substituted through an autosomal recessive mode of transmission. Structural and functional analysis of the mutant ERα revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERα. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients.

Conclusion: Description and analysis of this family of patients with mutant ERα provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.

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Figures

Figure 1.
Figure 1.
Phenotypic features of the proband, pedigree of the consanguineous family, and ESR1 sequence analysis. (A) Absence of breast development (Tanner stage I), mild adipomastia, and the presence of chest acne are shown from examination of the proband at age 25 years. (B) The pedigree of the proband (arrow) and her family. The double line indicates consanguinity. The triangle indicates miscarriage. Circles denote female family members; squares denote male family members. Solid symbols illustrate homozygous affected patients, and half-solid symbols represent family members who were heterozygous for ERS1 mutation. (C) The results of sequencing of the ESR1 gene in affected members of the proband’s family. Nucleotides are labeled with 1-letter symbols at the top of the chromatogram, with the corresponding double-stranded nucleotide sequences below. The arrow shows the homozygous mutant genotype resulting in a nucleotide change from G to A at complementary DNA nucleotide 1181 (GenBank accession number, NM_000125.3). Below, the 8 coding exons of the ESR1 gene and the corresponding domains of ERα protein are schematically represented. Arrows indicate the nucleotide (c.1181G>A) and residue (p.Arg394His) changes in affected patients. (D) Alignment of the Arg (R) 394 residue in ERα protein of other species, indicating complete conservation among species. DBD, DNA binding domain; LBD, ligand binding domain; NTD, N-terminal domain.
Figure 2.
Figure 2.
Functional analysis of the ESR1 mutation. (A) A representative western blot analysis of whole cell lysates detecting the presence of WT and mutant ER after transient transfection in HEK293T cells. Control corresponds to untransfected HEK293T cells. Expression of α-tubulin was also analyzed as a control. (B) 17β-estradiol dose-response curves of transactivation of ERE-luciferase (ERE upstream of luciferase) reporter constructs in transiently transfected HEK293T cells, revealing greatly reduced sensitivity of the ERα mutant compared with WT ERα. 17β-estradiol dose-response curves (0.1 pM to 1 µm) were generated in sextuplicate. Experiments were repeated 3 times. (C) The transcriptional activity of ERα ligand–activated R394H mutant (blue) never reached that of the WT ERα (red), regardless of the ligand (5 nM) indicated in the x-axis. Results are mean ± standard error of the mean of 3 independent ERE-luciferase reporter assays performed in sextuplicate. Dotted line represents the 100% maximal transcriptional activity of WT ERα. Statistical comparison between WT and R394H ERα mutant reveals significant difference for each experimental condition. (D) Estradiol within the ligand-binding cavity of the WT (upper panel) and the R394H mutant hERα (lower panel). From the N- to the C-terminus of the domain, the secondary structure elements are represented as ribbons with a blue-green-yellow color gradient. Only residues involved in estradiol anchoring are shown. Red dashed lines indicate hydrogen bonds between estradiol and the hERα residues. The figures were generated using PyMOL software (www.rcsb.org/pdb).
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