Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children Anu Bashamboo, Caroline.

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Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children Anu Bashamboo, Caroline Eozenou, Anne Jorgensen, Joelle Bignon-Topalovic, Jean-Pierre Siffroi, Capucine Hyon, Attila Tar, Péter Nagy, Janos Sólyom, Zita Halász, Annnabel Paye-Jaouen, Sophie Lambert, David Rodriguez-Buritica, Rita Bertalan, Laetitia Martinerie, Ewa Rajpert-De Meyts, John C. Achermann, Ken McElreavey The American Journal of Human Genetics Volume 102, Issue 3, Pages 487-493 (March 2018) DOI: 10.1016/j.ajhg.2018.01.021 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Identification of Three Individuals with 46,XX DSD and Heterozygous Frameshift Mutations in NR2F2 (A) Representative Sanger sequence chromatograms of individuals 1–3 showing the positions of the frameshift mutations. (B) Histology of the right gonad of individual 3 showing testicular tubule-like structures surrounded by stromal-like tissue (scale bar corresponds to 100 μm). (C) Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) of individual 3. (D) Uterus (arrow) of individual 2 observed by MRI. (E) Pelvic radiography of individual 3 showing the vagina (V) and a short urogenital sinus (UrS). (F) Schematic representation of COUP-TF2 showing the main functional domains and the position and downstream consequences of the three frameshift mutations. The first zinc finger motif is highlighted in green in the sequence alignment. The transcript ID is GenBank: NM_021005.3. The American Journal of Human Genetics 2018 102, 487-493DOI: (10.1016/j.ajhg.2018.01.021) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Protein Localization of COUP-TF2 and FOXL2 during Early Human Ovarian Development (A–C) Immunofluorescence showing protein localization of COUP-TF2 (green) and FOXL2 (red) at gestational week (GW) 9+1. (D–F) Immunohistochemistry at GW 9+5. Extensive staining of COUP-FT2 is observed in the stromal cell population of the developing fetal ovary. At both stages there appears to be a mutually exclusive presence of FOXL2 and NR2F2, suggesting they mark different somatic cell populations. Dashed box in (A) and (C) indicates the position of the expanded views. Nuclei are counterstained with DAPI. Fetal age was determined by scanning crown-rump length and by evaluation of foot length.34 Sex of fetal samples was determined by PCR for SRY as previously reported.35 Immunofluorescence was performed as previously described.36 Primary antibodies used were COUP-TFII/NR2F2 (Perseus Proteomics, PP-H7147-60, diluted 1:100) and FOXL2 (a kind gift from Dagmar Wilhelm, diluted 1:100). Negative controls were included and processed with the primary antibody replaced by the dilution buffer alone. None of the negative control slides showed staining. Fluorescent images were captured using an Olympus BX61 microscope (Olympus) with the Cell Sens Dimension software v.1.16. The American Journal of Human Genetics 2018 102, 487-493DOI: (10.1016/j.ajhg.2018.01.021) Copyright © 2018 The Authors Terms and Conditions