Identification and functional study of FOXC1 variants in Chinese families with glaucoma

Abstract

This study aimed to identify the disease‐causing gene of three Chinese families with glaucoma. Whole exome sequencing was performed on the probands and detected three different variants (c.405C>A (p.Cys135Ter), c.851G>T (p.Ser284Ile), and c.392C>T (p.Ser131Leu)) in FOXC1 as a causative gene of glaucoma, and Sanger sequencing was performed for verification and cosegregation analysis. Three in silico tools all predicted these two missense variants to be probably disease‐causing. Western blot analysis, immunofluorescence, and dual‐luciferase assay were further used to evaluate the effect of FOXC1 missense variants, and demonstrated that the two variants resulted in decreased transactivation activity of FOXC1 although the variants had no effect on the protein amount and the nucleus subcellar localization of FOXC1 compared with the wild type, which implies that both of two variants may be probably pathogenic. In this study, we reported two novel FOXC1 variants as well as a reported variant and the phenotypes associated to these variants, which expands the spectrum and relevant phenotypes of FOXC1 variants. Additionally, the functional analysis of FOXC1 variants provides further insight into the possible pathogenesis of anterior segment anomaly related to FOXC1.

De Novo Mosaic 6p23-p25.3 Tetrasomy Caused by a Small Supernumerary Marker Chromosome Presenting Trisomy Distal 6p Phenotype: A Case Report and Literature Review

“…FOXC1 (OMIM 601090) is located at 6p25.3 and has been shown to play a role in the regulation of embryonic and ocular development. A recent study suggests that truncating variants of FOXC1 causes anterior segment dysgenesis and cardiac anomalies [ 21 ]. Similarly, in previous reports, eye abnormalities are suggested to be an important component of the phenotype of distal 6p duplication, including congenital cataracts, colobomas, blepharoptosis, and blepharophimosis [ 10 , 12 ].…”