MUTATIONS IN SOX9 CAUSE BOTH AUTOSOMAL SEX REVERSAL AND CAMPOMELIC DYSPLASIA

The human testis determining factor (SRY) has been cloned from the Y c hromosome. This gene is a dominant inducer of male differentiation. Mu tations in the SRY gene result in an XY individual developing as a sex reversed phenotypic female. Sex reversal in humans can also be caused by mutations located in autosomal or X-linked loci. One such sex-reve rsing locus (SRAI) is associated with the developmental disorder campo melic dysplasia (CD). Both these syndromes were mapped to human chromo some 17q by the identification of balanced reciprocal translocations i n five unrelated patients. The translocation breakpoint of one such XY -female CD patient was mapped and the region surrounding it cloned. Th e closest distal marker used to map the translocation breakpoint was t he SOX9 gene. Because of the close proximity of this gene to the break point, it was subjected to mutation analysis in patients without overt chromosome rearrangements. Analysis of DNA from these patients and th eir parents identified de novo mutations in the SOX9 gene in patients with both autosomal sex reversal and CD. This showed that mutations in the SOX9 gene are responsible for both syndromes.