FOXL2 mutation screening in a large panel of POF patients and XX males.

Premature ovarian failure (POF) is defined as amenorrhoea for more than six months associated with raised gonadotrophins before the age of 40 years. This condition affects 1% of women in the general population. Most cases of POF are idiopathic and presumed to be genetic. Many X linked abnormalities are associated with idiopathic POF, including monosomy X in Turner syndrome and deletions and translocations implicating a number of X loci in POF. An autosomal dominant condition which is associated with POF is the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) (MIM 110100), linked to human chromosome 3q23. In BPES type I, a complex eyelid malformation is associated with POF, while in BPES type II the eyelid defect occurs as an isolated entity. The features of POF in BPES are similar to those observed in non-syndromic POF. However, the latter has not so far been linked to 3q23. Recently, Crisponi et al have shown that mutations in the forkhead transcription factor gene FOXL2 cause both BPES types I and II. A genotypephenotype correlation was shown for both types of BPES; mutations predicted to result in a truncated protein lead to BPES type I, while mutations predicted to result in an extended protein cause BPES type II. 4 FOXL2 is the first human autosomal gene of which dominant mutations have been shown to interfere with ovarian maintenance and POF. Expression studies have localised FOXL2 to follicular cells in the mouse ovary, being consistent with its presumed role in follicular development and maintenance. Considering the phenotypic spectrum of FOXL2 mutations in BPES (especially type I), it was logical to expect that they might also cause other phenotypes, including non-syndromic POF. 5 Moreover, the causal gene is a member of the forkhead transcription factor gene family and mutations in members of this diverse gene family have been shown to cause pleiotropic phenotypes. Human XX sex reversal without SRY is a rare condition and familial cases and chromosome rearrangements are scarce. However, in different domestic animals familial cases of XX sex reversal without SRY have been described, making them promising models for identifying genes that could be involved in human disorders. In 1996, the first mammalian gene involved in XX sex reversal was located through the mapping of the goat polled intersex syndrome (PIS) locus to goat chromosome 1q43. PIS is a disorder showing both a dominant absence of horns affecting both sexes and autosomal recessive XX sex reversal affecting only XX animals. The PIS locus is therefore a candidate for XX maleness. Vaiman et al proposed that goat PIS and human BPES could be encoded by a homologous gene, since the PIS locus at 1q43 proved to be the goat syntenic equivalent of the human BPES locus at 3q23 and since the PIS mutation was located in a 100 kb homologous interval of the BPES critical region. While the mapping data are consistent with this hypothesis, the phenotypes are more difficult to correlate. The interspecific phenotype difference could result from a different sex determining timing between both species, from different positions of the mutations in goats and humans, or could be explained by a more dosage sensitive system in humans. The involvement of FOXL2 in BPES and its expression pattern makes it a good candidate for PIS. As a consequence, we (and others) considered FOXL2 as a candidate to be evaluated in human XX males without SRY.