FOXP4 Variants Are Associated With Plateau Iris and Angle Closure Glaucoma

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Angle closure glaucoma (ACG) is a leading cause of vision loss, characterized by iris abnormalities and short axial lengths.
• While ACG is heritable, its underlying genetic risk factors remain largely unknown.
• This study focused on a family with a dominant inheritance pattern of ACG, plateau iris, and short axial lengths.

Purpose of the Study:

• To discover disease-causing genes for angle closure glaucoma (ACG).
• To investigate the role of genetic variants in the development of ACG.
• To identify novel genetic risk factors for ACG in a familial cohort.

Main Methods:

• Conducted pooled exome sequencing to identify coding variants.
• Evaluated the spatiotemporal expression of the candidate gene FOXP4 using immunostaining in mouse embryos.
• Assessed nuclear localization and transcriptional regulation of FOXP4 variants in cell lines and analyzed a large patient cohort for additional variants.

Main Results:

• Identified a likely pathogenic variant (c.1433A>G, p.Q478R) in the transcription factor FOXP4.
• FOXP4 is highly expressed in ocular structures critical for the drainage angle.
• The identified FOXP4 variant (p.Q478R) acts as a hypomorphic allele, retaining transcriptional activity but exhibiting cytosolic mislocalization, potentially indicating protein instability.

Conclusions:

• FOXP4 plays a crucial role in anterior segment development.
• Rare variants in FOXP4 are identified as risk factors for angle closure glaucoma.
• Further research into FOXP4's function may elucidate mechanisms of ACG pathogenesis.