Capra hircus

French Alpine chamoise goat, heterozygous for the PIS mutation (Photo INRA)

The genes of the PIS locus are the first genes to have been identified in the sexual inversion phenotype of the XX male, and they have proved to be primordial in early ovarian differentiation, in which very few of the actors are known at the moment.
An understanding of the mechanism of action of the 3 genes of this locus as well as the common regulatory region (the PIS region, which is deleted in mutant animals) is fundamental for advancing in the molecular dissection of sexual differentiation in mammals. Furthermore, this locus, in XY individuals, should represent the target for the determinant factor in testicle development, the SRY gene (Sex-determining Region of the Y chromosome). However, although SRY was discovered in 1989, no molecular target for this transcription factor has been identified to date.

This positional cloning project in a domestic animal was initiated by Professor Marc Fellous, who studies this type of pathology in humans.
Some patients have very masculine phenotypes in the absence of the SRY gene. These phenotypes are very similar to those observed in the goat, and may result from a dysfunction in the PIS region. In order to test this hypothesis, the important elements of the PIS region must be determined, in order to know where to look for mutations in humans.

Furthermore, the FOXL2 gene is responsible for BPES syndrome which is a heterozygous association of a malformation of the eyelids with an ovarian insufficiency in XX individuals. Although the majority of BPES patients present mutations in the FOXL2 ORF, some have translocations localized between FOXL2 and the PIS region. This supports the hypothesis that there are regulatory regions which are far from FOXL2, different from the PIS region, which does not influence the expression of FOXL2 in the eyelids.