Pathogenic Mechanisms of Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome in a Chinese Family with a Novel Missense FOXL2 Mutation

Abstract

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease, and the only known cause is the haploinsufficiency of the forkhead box L2 (FOXL2). The purpose of this study was to study the functional changes of a novel FOXL2 missense mutation in a Chinese family and provide insights into the pathogenic mechanisms. Methods: Two patients with typical clinical features within one family were enrolled in the present study. DNA was extracted from peripheral venous blood, and Sanger sequencing was used to detect the mutation. Then, the bioinformatic analyses were performed by the online software, and the experiments of western blotting, subcellular localization, luciferase reporter assays, and quantitative real-time PCR (qRT-PCR) were used to identify the function changes. Results: A novel FOXL2 missense mutation (c.292T>A) was detected in the forkhead domain. Subtle changes in structure and physicochemical properties were predicted in the bioinformatic analyses. However, the mislocalization of the mutant protein and impaired transcriptional activity in affecting the expressions of downstream genes explained the pathogenicity of this mutation. The odd-skipped related 2 transcription factor gene was more sensitive to the quantity change of FOXL2 and the presence of the detected mutation in the present study. Conclusions: This study not only expands the spectrum of FOXL2 mutations but also provides reference data and insights into the pathogenesis and subtyping of blepharophimosis-ptosis-epicanthus inversus syndrome.