• PMID: 29373757
• Gene Name: SOX8
• Condition: Reproductive anomalies, Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Reproductive anomalies, Male infertility

Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies

Portnoi MF, Dumargne MC, Rojo S, Witchel SF, Duncan AJ, Eozenou C, Bignon-Topalovic J, Yatsenko SA, Rajkovic A, Reyes-Mugica M, Almstrup K, Fusee L, Srivastava Y, Chantot-Bastaraud S, Hyon C, Louis-Sylvestre C, Validire P, de Malleray Pichard C, Ravel C, Christin-Maitre S, Brauner R, Rossetti R, Persani L, Charreau EH, Dain L, Chiauzzi VA, Mazen I, Rouba H, Schluth-Bolard C, MacGowan S, McLean WHI, Patin E, Rajpert-De Meyts E, Jauch R, Achermann JC, Siffroi JP, McElreavey K, Bashamboo A.

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 analysed 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 = 4.5 × 10-5) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with 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. FAU - Portnoi, Marie-France AU - Portnoi MF AD - APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France. AD - UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France. FAU - Dumargne, Marie-Charlotte AU - Dumargne MC AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France. FAU - Rojo, Sandra AU - Rojo S AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France. FAU - Witchel, Selma F AU - Witchel SF AD - Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. FAU - Duncan, Andrew J AU - Duncan AJ AD - Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. FAU - Eozenou, Caroline AU - Eozenou C AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France. FAU - Bignon-Topalovic, Joelle AU - Bignon-Topalovic J AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France. FAU - Yatsenko, Svetlana A AU - Yatsenko SA AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute. AD - Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. AD - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. FAU - Rajkovic, Aleksandar AU - Rajkovic A AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute. AD - Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. AD - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. FAU - Reyes-Mugica, Miguel AU - Reyes-Mugica M AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute. AD - Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. AD - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. FAU - Almstrup, Kristian AU - Almstrup K AD - University Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark. FAU - Fusee, Leila AU - Fusee L AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France. FAU - Srivastava, Yogesh AU - Srivastava Y AD - Genome Regulation Laboratory, Drug Discovery Pipeline, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. AD - Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. AD - 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. FAU - Chantot-Bastaraud, Sandra AU - Chantot-Bastaraud S AD - APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France. AD - UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France. FAU - Hyon, Capucine AU - Hyon C AD - APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France. AD - UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France. FAU - Louis-Sylvestre, Christine AU - Louis-Sylvestre C AD - Département Mère-Enfant, Institut Mutualiste Montsouris, Paris 75014, France. FAU - Validire, Pierre AU - Validire P AD - Département d'Anatomie Pathologique, Institut Mutualiste Montsouris, Paris 75014, France. FAU - de Malleray Pichard, Caroline AU - de Malleray Pichard C AD - Service d'Endocrinologie, Hôpital Cochin, Paris, France. FAU - Ravel, Celia AU - Ravel C AD - Biology of Reproduction, CHU Rennes, Rennes 35033, France. FAU - Christin-Maitre, Sophie AU - Christin-Maitre S AD - UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France. AD - Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, Paris 75012, France. FAU - Brauner, Raja AU - Brauner R AD - Université Paris Descartes and Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild, Paris 75019, France. FAU - Rossetti, Raffaella AU - Rossetti R AD - Department of Clinical Sciences & Community Health, University of Milan, Milan 20122, Italy. AD - Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy. FAU - Persani, Luca AU - Persani L AD - Department of Clinical Sciences & Community Health, University of Milan, Milan 20122, Italy. AD - Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy. FAU - Charreau, Eduardo H AU - Charreau EH AD - Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina. AD - Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina. FAU - Dain, Liliana AU - Dain L AD - Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina. AD - Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina. FAU - Chiauzzi, Violeta A AU - Chiauzzi VA AD - Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina. AD - Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina. FAU - Mazen, Inas AU - Mazen I AD - Department of Clinical Genetics, National Research Centre, Cairo 12622, Egypt. FAU - Rouba, Hassan AU - Rouba H AD - Human Genetics Unit, Institut Pasteur of Morocco, Casablanca 20250, Morocco. FAU - Schluth-Bolard, Caroline AU - Schluth-Bolard C AD - Genetic Services, Hopital Femme Mere Enfant, Bron 69677, France. FAU - MacGowan, Stuart AU - MacGowan S AD - Centre for Dermatology and Genetic Medicine, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. FAU - McLean, W H Irwin AU - McLean WHI AD - Centre for Dermatology and Genetic Medicine, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. FAU - Patin, Etienne AU - Patin E AD - Human Evolutionary Genetics, Institut Pasteur, Paris 75724, France. FAU - Rajpert-De Meyts, Ewa AU - Rajpert-De Meyts E AD - University Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark. FAU - Jauch, Ralf AU - Jauch R AD - Genome Regulation Laboratory, Drug Discovery Pipeline, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. AD - Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. AD - 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. FAU - Achermann, John C AU - Achermann JC AD - Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. FAU - Siffroi, Jean-Pierre AU - Siffroi JP AD - APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France. AD - UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France. FAU - McElreavey, Ken AU - McElreavey K AD - Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France.