A 11.7-kb deletion triggers intersexuality and polledness in goats

Mammalian sex determination is governed by the presence of the sex determin ing region Y gene (SRY) on the Y chromosome(1). Familial cases of SRY-negat ive XX sex reversal are rare in humans, often hampering the discovery of ne w sex-determining genes(2,3). The mouse model is also insufficient to corre ctly apprehend the sex-determination cascade, as the human pathway is much more sensitive to gene dosage(4-6). Other species might therefore be consid ered in this respect(7). In goats, the polled intersex syndrome (PIS) mutat ion associates polledness and intersexuality(8,9). The sex reversal affects exclusively the XX individuals in a recessive manner, whereas the absence of horns is dominant in both sexes. The syndrome is caused by an autosomal gene located at chromosome band 1q43 (ref. 9), shown to be homologous to hu man chromosome band 3q23 (ref. 10). Through a positional cloning approach, we demonstrate that the mutation underlying PIS is the deletion of a critic al 11.7-kb DNA element containing mainly repetitive sequences. This deletio n affects the transcription of at least two genes: PISRT1, encoding a 1.5-k b mRNA devoid of open reading frame (ORF), and FOXL2, recently shown to be responsible for blepharophimosis ptosis epicanthus inversus syndrome (BPES) in humans(11). These two genes are located 20 and 200 kb telomeric from th e deletion, respectively.