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^1,2. SOX9 contains a putative DNA-binding motif known as the high-mobility group (HMG) domain characterizing a whole class of transcription factors³. We show in cell transfection experiments that SOX9 can trans-activate transcription from a reporter plasmid through the motif AACAAAG, a sequence recognized by other HMG domain transcription factors³. 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 evolutionary conserved and rich in proline, glutamine and serine. With one exception⁴, all SOX9 nonsense and frame shift mutations described so far in CD/sex reversal patients^1,2,4 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.