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

Abstract

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.

Identification and functional analyses of a novel FOXL2 pathogenic variant causing blepharophimosis, ptosis, and epicanthus inversus syndrome

“…As a transcription factor, the FOXL2 was transferred into the nucleus for functioning, which corresponded with the result. In contrast, the mislocalization of the MT protein demonstrated the dysfunction of the mutant FOXL2 [18][19] . Next, the bioactivities of mutant FOXL2 as a transcription factor were researched by detecting the interactions with the downstream genes [15] .…”

Ovarian Reserve and ART Outcomes in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Patients With FOXL2 Mutations

“…Intriguingly, the 3 missense mutations previously reported in BPES type II were also found in our type I patients. These mutations have been shown to have subcellular mislocalization and adverse impacts on the transactivation of CYP19A1 , CCND2 , and StAR by in-vitro functional experiments ( 7 , 20 – 22 ). Therefore, the genotype-phenotype BPES classification correlation cannot be generalized.…”

Deletion of cis-regulatory Element in FOXL2 Promoter in a Chinese Family of Type II Blepharophimosis-ptosis-epicanthus Inversus Syndrome with Polydactyly

“…FOXL2-expressed Chinese Hamster Ovarian cells were maintained in a 1640 medium supplemented with 10% fetal calf serum and 1% penicillin/streptomycin. Luciferase assays were performed using the pGL3-basic Reporter System (Promega), following previously described methods 2 . A total of 3*104 Chinese Hamster Ovarian cells were plated in 500 ml of culture medium per well in 24-well plates.…”

“…Blepharophimosis, ptosis, and epicanthus inversus Syndrome (BPES) is an autosomal-dominant disease that affects the eyelids 1,2 . If left untreated, these characteristics are correlated with a high prevalence of amblyopia 3 .…”

“…Concurrently, to circumvent the limitations concomitant with this blind technique, numerous surgeons have incorporated the use of intraoperative ultrasound, as supported by previous studies. 2,3,8 Nevertheless, the complex 3-dimensional curvature of the nose and zygomatic arch presents challenges when scanning the adjacent facial bones. We applied a solid gel pad to augment the visualization of ultrasound images during surgery, thereby granting the surgeon better visual feedback and real-time video monitoring.…”