ESPE Abstracts (2016) 86 RFC15.1

A Novel Homozygous Mutation in the Domain AF-2 of Alpha Estrogen Receptor Gene (ESR1), Generating a Bio-Inactive ER[alpha] Mutant, Resulting in Estrogen Resistance with Complex Metabolic Phenotype

Eva Feigerlovaa, Henrik Laurellb, Hervé Mittrec, Marie-Laure Kottlerc, Marc Deshayesd, Patrick Balaguyere, Jean-François Arnalb, Richard Maréchauda, Samy Hadjadja & Pierre Gourdyb,f

aService d’Endocrinologie, Pole DUNE, CHU de Poitiers, Poitiers, France; bINSERM UMR 1048, I2MC, Université de Toulouse, Toulouse, France; cService de Génétique, CHU de Caen, Caen, France; dUnité de médecine de la reproduction, CHU de Poitiers, Poitiers, France; eINSERM UMR 1194, Université de Montpellier, Montpellier, France; fService de Diabétologie, Maladies Métaboliques et Nutrition, CHU de Toulouse, Toulouse, France

Context: The mouse ERα−/− knock-out model and rare human ESR1 gene mutations identified to date have demonstrated crucial role of ERα in control of energy homeostasis and glucose metabolism. Subjects with ERα deficiency show features of estrogen resistance (ESTRR) with continuous linear growth in adulthood.

Patient: We describe a 20-year-old female, with unknown family history, who presented with primary amenorrhea and lack of breast development (Tanner stage: B1-P4-A4). Pelvic MRI revealed a rudimentary uterus and polycystic ovaries. The patient presented with tall stature (180 cm), continuous linear growth and bone age of 12 years. Her BMI was 28 kg/m2 and she had increased abdominal adiposity assessed by DXA (trunk/limb fat ratio 1.3). Endocrine evaluations indicated ESTRR, with elevated LH (40 UI/l), FSH (44 UI/l), E2 (1670 pmol/l, reference values: 220–400), and hyperandrogenism (testosterone 7.7 nmol/l, delta-4-androstenedion 12.5 nmoL/l). Metabolic explorations revealed insulin resistance (HOMA-IR 11,8), elevated leptin (75 ng/ml), contrasting with normal adiponectin (3.1 ug/ml) and normal lipid profile. Hepatic triglyceride content measured by MR spectroscopy was of 7%.

Results: The patient’s phenotype was consistent with ERα deficiency. Sequencing of the ESR1 gene revealed a novel homozygous T to C transition in exon 10, which resulted in a p.Met543Thr missense mutation. Met543, a highly conserved residue, is within the ligand binding domain (AF-2, helix H12). Preliminary reconstitution studies indicate a significant decrease in transcriptional activity of the mutant protein after treatment with estradiol.

Conclusion: A novel missense ESR1 mutation, p.Met543Thr has been identified in a patient who presented with a complex phenotype consistent with ERα deficiency. Only two ESR1 mutations were reported in the literature to date. This new mutation resulted in a bio-inactive ERα variant. The phenotype of our patient, together with previously described cases, confirms the crucial role of ERα in pubertal growth as well as metabolic phenotype.