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

Autor:	Portnoi MF; APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France.; UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France., Dumargne MC; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Rojo S; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Witchel SF; Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA., Duncan AJ; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK., Eozenou C; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Bignon-Topalovic J; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Yatsenko SA; Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute.; Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Rajkovic A; Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute.; Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Reyes-Mugica M; Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Women's Research Institute.; Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Almstrup K; University Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark., Fusee L; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Srivastava Y; 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.; 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.; 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., Chantot-Bastaraud S; APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France.; UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France., Hyon C; APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France.; UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France., Louis-Sylvestre C; Département Mère-Enfant, Institut Mutualiste Montsouris, Paris 75014, France., Validire P; Département d'Anatomie Pathologique, Institut Mutualiste Montsouris, Paris 75014, France., de Malleray Pichard C; Service d'Endocrinologie, Hôpital Cochin, Paris, France., Ravel C; Biology of Reproduction, CHU Rennes, Rennes 35033, France., Christin-Maitre S; UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France.; Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, Paris 75012, France., Brauner R; Université Paris Descartes and Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild, Paris 75019, France., Rossetti R; Department of Clinical Sciences & Community Health, University of Milan, Milan 20122, Italy.; Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy., Persani L; Department of Clinical Sciences & Community Health, University of Milan, Milan 20122, Italy.; Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy., Charreau EH; Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina.; Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina., Dain L; Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina.; Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina., Chiauzzi VA; Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires C1428ADN, Argentina.; Department of Physiology, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina., Mazen I; Department of Clinical Genetics, National Research Centre, Cairo 12622, Egypt., Rouba H; Human Genetics Unit, Institut Pasteur of Morocco, Casablanca 20250, Morocco., Schluth-Bolard C; Genetic Services, Hopital Femme Mere Enfant, Bron 69677, France., MacGowan S; Centre for Dermatology and Genetic Medicine, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., McLean WHI; Centre for Dermatology and Genetic Medicine, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Patin E; Human Evolutionary Genetics, Institut Pasteur, Paris 75724, France., Rajpert-De Meyts E; University Department of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark., Jauch R; 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.; 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.; 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., Achermann JC; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK., Siffroi JP; APHP Département de Génétique Médicale, Hôpital Armand Trousseau, Paris 75012, France.; UPMC, University Paris 06, INSERM UMR_S933, Hôpital Armand Trousseau, Paris 75012, France., McElreavey K; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France., Bashamboo A; Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, Paris 75724, France.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2018 Apr 01; Vol. 27 (7), pp. 1228-1240.
DOI:	10.1093/hmg/ddy037
Abstrakt:	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.
Databáze:	MEDLINE
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