General Medical Information

Nature of X-Ovarian Maintenance Determinants

Joe Leigh Simpson

Clearly the X chromosome is necessary for ovarian maintenance, preventing premature germ cell attribution and permitting progression beyond meiotic pachytene.

Ultimately both the number of individual genes and their gene product(s) will be determined. This would have both prognostic as well as potential therapeutic value, given that recombinant technology allows synthesis of a protein gene product(s) once the DNA sequence is known. At present little is known about the nature of ovarian maintenance gene products. Jones proposed that a key gene product is DFFRX, located on Xp11.4 and homologous to a locus on Yq11.2. Both genes escaped inactivation in two de novo (X) deletions. James considered DFFRX an unlikely candidate after observing ovarian function despite haploinsufficiency; however, neither of the two cases of James were completely normal clinically, for which reason a role for DFFRX in gonadal development is not categorically excluded.

A candidate gene for a role in ovarian maintenance is the human homologue of the Drosophila melanogaster gene diaphanous (dia). This gene causes sterility in male and female Drosophila. Sequence comparisons between dia and the relevant human expressed sequence tag (EST) DRE25 show significant homology. DRE25 in turn maps to human Xq22. As already noted, Xq22 is a key region for ovarian maintenance. Drosophila dia is a member of a family of proteins that help establish cell polarity, govern cytokinesis, and reorganize the actin cytoskeleton. Studying familial POF, an Xq21/autosome translocation alluded to earlier was found to be associated with disruption of DRE25.

A broader biologic question can be posed concerning X-ovarian maintenance determinants. Do the various regions contain gene(s) coding for different gene products? If so, all these genes might be either essential or at least contribute to normal ovarian differentiation. If different genes exist, the prospect of alternative therapeutic options is raised, given that various gene products eventually will all be synthesized. However, it would seem hazardous evolutionarily if perpetuation of the species were to depend on transcription and translation of an entire cascade of ovarian differentiation genes, perturbation of any of which would be deleterious if not lethal (genetically). Moreover, ovarian disturbance associated with many X-deletions is rarely complete. Proximal deletions involving either Xp or proximal Xq may be associated with complete ovarian failure, but more distal deletions are more likely to be associated with POF or normal ovarian function.

Teleologically, it might be more attractive if all X-ovarian maintenance determinants were to produce the same gene product or perhaps products capable of interaction (e.g., dimerization). This would seem to be more conservative evolutionarily, for mutation or deletion of a single locus would not be singularly catastrophic. If such a scenario were true, an ineluctable corollary would be that the X-ovarian genes act in threshold fashion and thus exert their primary effect through an autosomal gene. One mode of action might involve transcriptional or translational regulation of DNA-binding proteins.