The Role of SOX9 in Autosomal Sex Reversal and Campomelic Dysplasia

In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome campomelic dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus (SRA1) and a campomelic dysplasia locus (CMPD1) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed campomelic dysplasia patient revealed its proximity to SOX9, a gene which is related to SRY. Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1/CMPD1 and the role of SOX9 mutations in sex reversal and campomelic dysplasia are discussed.