title: Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
abstract: Haploinsufficiency for SOX9 has recently been identified as the cause for both campomelic dysplasia (CD), a human skeletal malformation syndrome, and the associated autosomal XY sex reversal. SOX9 contains a putative DNA-binding motif known as the high-mobility group (HMG) domain characterizing a whole class of transcription factors. We show in cell transfection experiments that SOX9 can transactivate transcription from a reporter plasmid through the motif AACAAAG, a sequence recognized by other HMG domain transcription factors. By fusing all or part of SOX9 to the DNA-binding domain of yeast GAL4, the transactivating function was mapped to a transcription activation (TA) domain at the C terminus of SOX9. This non-acidic TA domain is evolutionarily conserved and rich in proline, glutamine and serine. With one exception, all SOX9 nonsense and frame shift mutations described so far in CD/sex reversal patients lead to truncation of the TA domain, suggesting that impairment of gonadal and skeletal development in these cases results, at least in part, from loss of transactivation of genes downstream of SOX9.
authors.affiliation: Institute of Human Genetics, University of Freiburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Südbeck
authors.forename: M L
authors.initials: ML
authors.lastname: Schmitz
authors.forename: P A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: G
authors.initials: G
authors.lastname: Scherer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002457:Cell Extracts; D002478:Cells, Cultured; D017124:Conserved Sequence; D004268:DNA-Binding Proteins; D012734:Disorders of Sex Development; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000882:Haplorhini; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002457:Cell Extracts; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D006609:High Mobility Group Proteins; D011993:Recombinant Fusion Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors