Identification of the first gene involved in Female Infertility

Female Infertility is a common condition affecting about 1% of women worldwide. The majority of these women have an alteration of their ovarian function. In spite of the relevance of this disorder the causes of the infertility are still unknown in the most part of the cases.
With our research we have been able to identify a new gene, FOXL2, representing the first gene involved in the development and maintenance of ovarian follicles. The study of this gene will lead to new prospective for the understanding of the molecular mechanisms responsible for Ovarian Failure causing Female Infertility. While FOXL2 mutations account for a small fraction Ovarian Failure, the study of its pathway will probably lead not only to new diagnostic tools for early diagnosis but also to new development of targeted therapeutic protocols for a disorder for which no treatment is currently available.
Blefarophimosis Ptosis Epicanthus Inversus Syndrome (BPES) is a rare mendelian disorder showing eyelid abnormalities and Ovarian Failure which is responsible for female infertility exclusively in affected females. Our group adopted a Positional Cloning approach to identify the gene responsible for BPES. Starting from a male patient with chromosome 3 alteration, we have been able to clone FOXL2, a new transcription factor belonging to the Forkhead family, which is expressed exclusively in the ovary and the developing eyelids. Today for the first time is possible to carry out molecular diagnosis for BPES.
We collaborated with several groups, both in Italy and abroad. In particular several Italian and French groups provided the DNA samples from BPES patients. The collaboration with an American group facilitated the search for the gene on chromosome 3.
The presence of two FOXL2 active copies is necessary for the development and the maintenance of the right number of ovarian follicles. It is clear that this transcription factor plays an important role in the regulation of the activity of other genes which are themselves involved in proper ovarian function. The study of FOXL2 pathway will allow a better understanding of ovarian development and its alterations in Female Infertility. FOXL2 could be used in the future as a marker of female fertility with which evaluate the female reproductive potential. On the long run it will be possible to develop targeted therapy for sterility through the reactivation of the FOXL2 pathway.
The project is partially founded by the Telethon Foundation.
Details of the discovery have been published on Nature Genetics (Crisponi et al. 27: 159-166; 2001).