The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome

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In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

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Figure 1: Physical map of the BPES region.
Figure 2: Predicted amino acid sequence and domain alignment of FOXL2.
Figure 3: Segregation analysis of FOXL2 mutations in type I and type II BPES families.
Figure 4: Ovary-specific expression of FOXL2 in human tissues.
Figure 5: Foxl2 expression in mouse tissues in whole-mount in situ hybridization.
Figure 6: Foxl2 expression in mouse embryo section.
Figure 7: Foxl2 expression in mouse adult ovary.
Figure 8: Eyelid defects in a BPES family.

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We thank the families for participation; G. Crisponi for photographing BPES patients and whole-mount mouse embryo in situ samples; S. Orrù for sectioning and photographing mouse embryo sections; S. McMillan and the Telethon screening service, Milan, for BAC and PAC screening; a group led by E. Chen and P. Ma, with assistance from V. Belonogoff, for long-range sequencing; and G. Sebastio, L. Boccone and M.R. Piemontese. This work was supported by the Telethon Grant N. E357 and E867 to G.P. and Assessorato Igiene e Sanità, Legge Regionale n.11 del 30.04.1990.

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Correspondence to Giuseppe Pilia.

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Crisponi, L., Deiana, M., Loi, A. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27, 159–166 (2001) doi:10.1038/84781

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