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Mutational Analysis of the SOX9 Gene in Campomelic Dysplasia and Autosomal Sex Reversal: Lack of Genotype/Phenotype Correlations

Meyer, Jobst ; Südbeck, Peter ; Held, Marika ; Wagner, Thomas ; Schmitz, M. Lienhard ; Dagna Bricarelli, Franca ; Eggermont, Ephrem ; Friedrich, Ursula ; Haas, Oskar A. ; Kobelt, Albrecht ; Leroy, Jules G. ; Van Maldergem, Lionel ; Michel, Erik ; Mitulla, Beate ; Pfeiffer, Rudolf A. ; Schinzel, Albert ; Schmidt, Heinrich ; Scherer, Gerd

In: Human Molecular Genetics, 1997, vol. 6, no. 1, p. 91-98

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    Titre
    • Mutational Analysis of the SOX9 Gene in Campomelic Dysplasia and Autosomal Sex Reversal: Lack of Genotype/Phenotype Correlations
    Auteur
    • Meyer, Jobst. Institute of Human Genetics, University of Freiburg, D-79106 Freiburg, Germany
    • Südbeck, Peter. Institute of Human Genetics, University of Freiburg, D-79106 Freiburg, Germany
    • Held, Marika. Institute of Human Genetics, University of Freiburg, D-79106 Freiburg, Germany
    • Wagner, Thomas. Institute of Human Genetics, University of Freiburg, D-79106 Freiburg, Germany
    • Schmitz, M. Lienhard. Institut für Biochemie und Molekularbiologie, University of Freiburg, D-79106 Freiburg, Germany
    • Dagna Bricarelli, Franca. Ente Ospedaliero Ospedali Galliera, I-16128 Genova, Italy
    • Eggermont, Ephrem. Department of Pediatrics, University-Hospital Gasthuisberg, Catholic University Leuven, B-3000 Leuven, Belgium
    • Friedrich, Ursula. institute of Human Genetics, University of Aarhus, DK-8000 Aarhus, Denmark
    • Haas, Oskar A.. Forschungsinstitut fur krebskranke Kinder, St Anna Kinderspital, A-1090 Wien, Austria
    • Kobelt, Albrecht. Abt. fur Klinische Genetik und Pranataldiagnostik, Frauenklinik Chemnitz, D-09009 Chemnitz, Germany
    • Leroy, Jules G.. Department of Pediatrics, University-Hospital, Gent University, B-9000 Gent, Belgium
    • Van Maldergem, Lionel. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, B-6280 Loverval, Belgium
    • Michel, Erik. Kinderkrankenhaus, Krankenhaus Neukolln, D-12051 Berlin, Germany
    • Mitulla, Beate. Humangenetische Beratungsstelle, Klinikum Suhl, D-98503 Suhl, Germany
    • Pfeiffer, Rudolf A.. Institute of Human Genetics, University of Erlangen-Nurnberg, D-91054 Erlangen, Germany
    • Schinzel, Albert. Institute of Medical Genetics, University of Zurich, CH-8001 Zurich, Switzerland
    • Schmidt, Heinrich. Universitats-Kinderklinik, Universitat Munchen, D-80337 Munchen, Germany
    • Scherer, Gerd. Institute of Human Genetics, University of Freiburg, D-79106 Freiburg, Germany
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 1997, vol. 6, no. 1, p. 91-98. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303081
    Summary
    It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations