title: Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.
abstract: Campomelic dysplasia (CD) is a semilethal osteochondrodysplasia, characterized by skeletal anomalies that include bending of the long bones, and by XY sex reversal. CD results from haploinsufficiency for the transcription factor SOX9, a key regulator at various steps of cartilage differentiation and of early testis development. Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain. We present two CD patients with de novo mutations in a conserved region preceding the HMG domain. A long-term survivor with the acampomelic form of CD has an A76E amino acid substitution, while a severely affected CD patient had an in-frame deletion of amino acid residues 66-75. The conserved domain has been shown to function in the related transcription factor SOX10 as a DNA-dependent dimerization domain. We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap. Dimerization and the resulting capacity to activate promoters via dimeric binding sites is lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. These findings establish the dimerization domain as the third domain essential for SOX9 function during chondrogenesis.
authors.affiliation: Institut für Biochemie, Universität Erlangen, D-91054 Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sock
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Pagon
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Keymolen
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.forename: Michael
authors.initials: M
authors.lastname: Wegner
authors.forename: Gerd
authors.initials: G
authors.lastname: Scherer
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D020219:Chondrogenesis / Q000502:physiology*; D024161:Collagen Type XI / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D016326:Extracellular Matrix Proteins; D005260:Female; D005786:Gene Expression Regulation; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins; D010009:Osteochondrodysplasias / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D020218:Response Elements; D055758:SOX9 Transcription Factor; D055757:SOXE Transcription Factors; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D024161:Collagen Type XI; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D006609:High Mobility Group Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D011506:Proteins; C527923:SOX10 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D004247:DNA