Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.

Autor:	Kim GJ; Institute of Human Genetics, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany., Sock E; Institute of Biochemistry, University of Erlangen-Nürnberg, Erlangen, Germany., Buchberger A; Department of Cell and Molecular Biology, Institute of Biochemistry and Biotechnology, University of Braunschweig, Braunschweig, Germany., Just W; Institute of Human Genetics, University of Ulm, Ulm, Germany., Denzer F; Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, Ulm, Germany., Hoepffner W; University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany., German J; Department of Pediatrics, Cornell University, New York, USA., Cole T; Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, UK., Mann J; Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK., Seguin JH; Pediatrix Medical Group of Ohio, Columbus, Ohio, USA., Zipf W; Central Ohio Pediatric Endocrinology and Diabetes Services (COPED), Columbus, Ohio, USA., Costigan C; National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Dublin, Ireland., Schmiady H; Klinik für Gynäkologie, Charité, Frauenklinik Campus Virchow-Klinikum, Berlin, Germany., Rostásy M; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Kramer M; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Kaltenbach S; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Rösler B; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Georg I; Institute of Human Genetics, University of Freiburg, Freiburg, Germany Area of Human DNA Variability, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain., Troppmann E; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Teichmann AC; Institute of Human Genetics, University of Freiburg, Freiburg, Germany., Salfelder A; Department of Pediatrics, Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany., Widholz SA; Institute of Biochemistry, University of Erlangen-Nürnberg, Erlangen, Germany., Wieacker P; Institute of Human Genetics, Westfälische Wilhelms Universität Münster, Münster, Germany., Hiort O; Department of Pediatric and Adolescent Medicine, University of Lübeck, Lübeck, Germany., Camerino G; Dipartamento di Patologia Umana ed Ereditaria, Biologia Generale e Genetica Medica, Pavia, Italy., Radi O; Dipartamento di Patologia Umana ed Ereditaria, Biologia Generale e Genetica Medica, Pavia, Italy., Wegner M; Institute of Biochemistry, University of Erlangen-Nürnberg, Erlangen, Germany., Arnold HH; Department of Cell and Molecular Biology, Institute of Biochemistry and Biotechnology, University of Braunschweig, Braunschweig, Germany., Scherer G; Institute of Human Genetics, University of Freiburg, Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2015 Apr; Vol. 52 (4), pp. 240-7. Date of Electronic Publication: 2015 Jan 20.
DOI:	10.1136/jmedgenet-2014-102864
Abstrakt:	Background: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. Results: By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. Conclusions: Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination. (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
Databáze:	MEDLINE
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