SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; p<0.05) and POI (5.06%; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI.
Human molecular genetics. 2018 Jan 24 [Epub ahead of print]
Marie-France Portnoi, Marie-Charlotte Dumargne, Sandra Rojo, Selma F Witchel, Andrew J Duncan, Caroline Eozenou, Joelle Bignon-Topalovic, Sventlana A Yatsenko, Aleksandar Rajkovic, Miguel Reyes-Mugica, Kristian Almstrup, Lelia Fusee, Yogesh Srivastava, Sandra Chantot-Bastaraud, Capucine Hyon, Christine Louis-Sylvestre, Pierre Validire, Caroline de Malleray Pichard, Celia Ravel, Sophie Christin-Maitre, Raja Brauner, Raffaella Rossetti, Luca Persani, Eduardo H Charreau, Liliana Dain, Violeta A Chiauzzi, Inas Mazen, Hassan Rouba, Caroline Schluth-Bolard, Stuart MacGowan, W H Irwin McLean, Etienne Patin, Ewa Rajpert-De Meyts, Ralf Jauch, John C Achermann, Jean-Pierre Siffroi, Ken McElreavey, Anu Bashamboo
APHP Département de Génétique médicale, Hôpital Armand Trousseau, Paris, 75012, France., Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris, France., Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA., Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, U.K., Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., University Department of Growth and Reproduction, Rigshospitalet, DK-2100, Copenhagen, Denmark., Genome Regulation Laboratory, Drug Discovery Pipeline, [2]Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China., Département Mère-Enfant, Institut Mutualiste Montsouris, Paris, France., Département d'Anatomie Pathologique, Institut Mutualiste Montsouris, Paris, France., Service d'Endocrinologie, Hôpital Cochin, Paris, France., Biology of Reproduction, CHU Rennes, Rennes, France., UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris, 75012, France., Université Paris Descartes and Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France., Department of Clinical Sciences & Community Health, University of Milan, 20100 Milan, Italy. Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149 Milan, Italy., Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS), Dr. Carlos G. Malbrán, Buenos Aires, Argentina; Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires, Argentina., National research Centre, Cairo, Egypt., Human Genetics Unit, Institut Pasteur of Morocco, Casablanca, 20100, Morocco., Genetic Services, Hopital Femme, Mere, Enfant, 69677, Bron, France., Centre for Dermatology and Genetic Medicine, School of Life Sciences, University of Dundee, Dundee, U.K., Human Evolutionary Genetics, Institut Pasteur, Paris, France.