Novel FOXL2 mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome with premature ovarian insufficiency

BackgroundBlepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a malformation of the eyelids. Forkhead BoxL2 (FOXL2) is the only gene known to be associated with BPES. MethodsWe identified two Han Chinese BPES families with premature ovarian insufficiency (POI). Sanger sequencing and invitro functional analysis were performed to identify the genetic cause. ResultsSanger sequencing identified two novel mutations (c.462_468del, c.988_989insG) in FOXL2, one in each family. The invitro functional analysis confirmed that both novel mutations were associated with impaired transactivation of downstream genes. Specifically, the single-base insertion, c.988_989insG, led to subcellular mislocalization and aggregation of the encoded protein, which validated the hypothesis that the two novel FOXL2 mutations are deleterious and associated with POI in the two BPES families. ConclusionThe novel mutations identified in the present study will enhance the present knowledge of the mutation spectrum of FOXL2. The invitro experiments provide further insights into the molecular mechanism by which the two new variants mediate disease pathogenesis and may contribute to elucidating the genotype-phenotype correlation between the two novel FOXL2 mutations and POI.