New bedfellows in the mammalian sex-determination affair

Abstract

In eutherian mammals, sex determination is defined as the initiation of testis development. This is because all subsequent sexual differentiation is dependent upon and secondary to this initial event, which is controlled by the presence or absence of the SRY gene on the Y chromosome 1. SRYis thought to exert its dominant effect by diverting the development of the indifferent gonad from the female (default) pathway to the male pathway of development. Several human loci not located on the Y chromosome have been known for many years to be associated with disturbances in gonadal development. Recently, genes have been isolated at two of these loci, both of which appear to exert their effect on sex determination through an altered dosage in XY individuals who carry a normal SRYgene on their Y chromosome. One of these genes maps to a locus on chromosome 17, SRA1, which is associated with the skeletal malformation syndrome campomelic dysplasia (CD), that is sometimes accompanied by a gradation of genital defects or primary gonadal dysgenesis 2. By cloning the breakpoints of several translocations associated with CD and sex reversal, soxg, a gene continuing an SRY-like HMG (high mobility group) box domain, has been identified at this locus 3. This gene was analysed by assaying for single-strand conformation polymorphisms and by direct sequencing for mutations in CD patients3,4. Mutations within the gene involving premature stop codons, amino acid substitutions, one splice acceptor and one donor alteration have been identified, and all are expected to result in loss of function of the SOX9 gene product. All the mutant individuals except one were heterozygous, carrying one normal allele of SOXg. These findings suggest that both CD and sex reversal result from a haploinsufficiency of the gene product rather than from a dominant negative effect. The second gene that has recently been isolated is DAX1, an X-linked gene responsible for adrenal hypoplasia congenita (AHC) 5,6. This gene maps to Xp21, a critical interval of the X chromosome that has been known for some time to cause male to female sex reversal when it is duplicated 7. Mutational analysis of DAXI in patients with X-linked AHC has demonstrated that functional disturbance of this gene in the absence of any other detectable change in Xp21 also results in hypogonadotropic hypogonadism (HHG), and lends credence to the idea that DAX1 might be the gene responsible for the dosage-sensitive sex reversal associated with the DSS locus on Xp21.