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

ABSTRACT: Context:Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) ? and ?, 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 17?-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 ER? revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ER?. 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 ER? provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.

SUBMITTER: Bernard V

PROVIDER: S-EPMC5413105 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Bernard Valérie V Kherra Sakina S Francou Bruno B Fagart Jérôme J Viengchareun Say S Guéchot Jérôme J Ladjouze Asmahane A Guiochon-Mantel Anne A Korach Kenneth S KS Binart Nadine N Lombès Marc M Christin-Maitre Sophie S

The Journal of clinical endocrinology and metabolism 20170101 1

<h4>Context</h4>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.<h4>Objective</h4>The study's aim was to describe a family in which 3 members presented with estrogen insensitivity.<h4>Design and setting</h4>Clinical evaluation and genetic and mutational analysis were performed in an academic medical center.<h4>Patients and int ...[more]

PMID: 27754803

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Project description:The E693? (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid ? (A?) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of A? oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than A? accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented A? oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of A? accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

Dataset Information

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

Publications

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

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