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

Kim GJ, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, German J, Cole T, Mann J, Seguin JH, Zipf W, Costigan C, Schmiady H, Rostasy M, Kramer M, Kaltenbach S, Roesler B, Georg I, Troppmann E, Teichmann AC, Salfelder A, Widholz SA, Wieacker P, Hiort O, Camerino G, Radi O, Wegner M, Arnold HH, Scherer G (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Journal of Medical Genetics BMJ Publishing Group

Book Volume: 52

Pages Range: 240-7

Journal Issue: 4

DOI: 10.1136/jmedgenet-2014-102864

Abstract

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.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.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.

Authors with CRIS profile

Elisabeth Sock Lehrstuhl für Biochemie und Pathobiochemie Michael Wegner Lehrstuhl für Biochemie und Pathobiochemie

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Technische Universität Braunschweig DE Germany (DE) Universität Ulm DE Germany (DE) Universitätsklinikum Ulm DE Germany (DE) Universität Leipzig DE Germany (DE) Cornell University US United States (USA) (US) University of Birmingham GB United Kingdom (GB) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Pediatrix Medical Group US United States (USA) (US) Central Ohio Pediatric Endocrinology and Diabetes Services (COPEDS) US United States (USA) (US) Our Lady's Children's Hospital IE Ireland (IE) Charité - Universitätsmedizin Berlin DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Universität zu Lübeck DE Germany (DE) Università degli Studi di Pavia IT Italy (IT)

How to cite

APA:

Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W.,... Scherer, G. (2015). Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development. Journal of Medical Genetics, 52(4), 240-7. https://doi.org/10.1136/jmedgenet-2014-102864

MLA:

Kim, Gwang-Jin, et al. "Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development." Journal of Medical Genetics 52.4 (2015): 240-7.

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