Functional Studies of Novel FOXL2 Variants in Chinese Families With Blepharophimosis–Ptosis–Epicanthus Inversus Syndrome

The blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease mainly caused by FOXL2 variants. This genetic disorder is usually characterized by eyelid malformation and ovarian dysfunction. However, no reliable genotype/phenotype correlations have been established considering the ovarian phenotype. Here, we detected 15 FOXL2 variants including nine novel ones from 7 families and 8 sporadic cases, which expanded the spectrum of FOXL2 variants and identified a potential clinical cause. Functional studies, with respect to the effect of FOXL2 on the StAR promoter, showed that non-sense variants that lead to protein truncation before the polyalanine tract and missense variants [c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), c.320G > A; p.(Ser107Asn), and c.335T > A; p.(Phe112Tyr)] within the central portion of the FOXL2 forkhead domain significantly affect its suppressor activity. Such changes may explain the mechanism underlying a more severe phenotype, more likely to result in BPES type I. Furthermore, the missenses variants c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), and c.320G > A; p.(Ser107Asn) were not able to transactivate OSR2, which is consistent with the eyelid malformation in these patients. The results from our cohort have expanded the spectrum of FOXL2 variants and have provided insights into genotype/phenotype correlations.

Cooption of polyalanine tract into a repressor domain in the mammalian transcription factor HoxA11

An enduring problem in biology is explaining how the functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem-lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins. These results suggest that long polyalanine tracts, which are common in transcription factors and often associated with disease, may generally function as repressor domains and can contribute to the diversification of transcription factor functions despite the deleterious consequences of polyalanine tract expansion.Research HighlightsWe show that a polyalanine track in HoxA11 evolved into a repressor domain in mammals through an increase in alanine repeat number, indicating that transcription factors can evolve novel functions despite the potential deleterious consequences associated with amino acid repeats.