THE ROLE OF SOX9 IN AUTOSOMAL SEX REVERSAL AND CAMPOMELIC DYSPLASIA

In eutherian mammals, the Y-chromosome gene SRY is required for induct ion of testis development. Although the Y chromosome is sex determinin g, loci located elsewhere in the genome participate in the complex cas cade of genetic interactions required to form a testis, Male to female sex reversal (46,XY females) occurs at a high frequency in individual s afflicted with the skeletal malformation syndrome campomelic dysplas ia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus (SRA1) and a campomelic dysp lasia locus (CMPD1) to the long arm of human chromosome 17. The molecu lar cloning of a translocation breakpoint in a sex reversed campomelic dysplasia patient revealed its proximity to SOX9, a gene which is rel ated to SRY. Analysis of SOX9 in patients without chromosomal rearrang ements demonstrated single allele mutations in sex reversed campomelic individuals, linking this gene with both bone formation and control o f testis development. Identification of SOX9 as SRA1/CMPD1 and the rol e of SOX9 mutations in sex reversal and campomelic dysplasia are discu ssed.