Mutated Autosomal Gene Results In Premature Ovarian Failure (POF)

Infertility due to premature ovarian failure (POF) is a relatively common disorder, affecting an estimated 1% of women. POF typically manifests itself in the cessation of menses before age 40, accompanied by elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). It is known to result from a variety of defects, including a lower-than-normal complement of follicles, increased follicular loss, or so-called 'resistant ovaries', in which follicles no longer mature and ovulate in response to FSH and LH. Although autoimmunity and irradiation are known causes of POF, the importance of genetic components has been suggested both by the finding of affected families and by its association with a variety of X-chromosome abnormalities.

Giuseppe Pilia, of the University of Cagliari (Italy), along with an international group of collaborators in Belgium, France, the United States, and elsewhere in Italy, have now identified an autosomal gene that, when mutated, results in POF (Nature Genetics, Vol. 27, Issue 2, 01 Feb 2001). The analysis of a syndrome characterized by an odd assortment of effects was the key to their finding. The syndrome, BPES type I, involves craniofacial abnormalities, eyelid defects and female infertility due to ovarian failure. Following up on previous studies in which a small region on chromosome 3 was identified as the region in which the critical gene is located, the researchers scrutinized two candidate genes, one of which, FOXL2, was found to be mutated in each affected member of four different type I BPES families. Consistent with ovarian dysfunction, FOXL2was found to be expressed almost exclusively in the ovary in adult humans. In mice, the gene is expressed at high levels in developing eyelids and in the follicle cells that surround and nourish the oocytes, suggesting that it is in some way required for the development and maintenance of the follicles.

As Robyn Prueitt and Andrew Zinn (University of Texas Southwestern Medical School, Dallas) point out in an accompanying News & Views article, several promising lines of investigation are now apparent. FOXL2 encodes a protein known as a transcription factor, which regulates the action of other genes. A number of peptide growth factors are co-expressed with FOXL2 in the ovary; the genes encoding one or more of these factors now represent candidate targets of FOXL2, and may turn out to be the critical medatior(s) of ovarian dysfunction. The production of a Foxl2-deficient mouse undoubtedly will be an important step toward identifying the precise mechanism whereby FOXL2 promotes the viability of ovarian follicles and prevents ovarian failure.

CONTACT:

Dr. Giuseppe Pilia
Instituto di Ricerca sulle Talassemie ed
Anemie Mediterranee CNR
Caligiari, Italy
Telephone: +39 070 6095 504
Fax: +39 070 503696
e-mail: pilia@unica.it

Dr. Andrew R. Zinn
McDermott Center for Human Growth and Development
Department of Internal Medicine
University of Texas South Western Medical School
Dallas, Texas, USA
Telephone: +1 (214) 648-1615
Fax: +1 (214) 648-1666
e-mail: andrew.zinn@utsouthwestern.edu

(C) Nature Genetics press release.

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