Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model

Area of Science:

• Neuroscience
• Genetics
• Ophthalmology

Background:

• Pathogenic NR2F1 variants cause Bosch-Boonstra-Schaaf Optic Atrophy Syndrome, a rare neurodevelopmental disorder.
• Visual loss is a key feature, but underlying molecular and cellular mechanisms remain poorly understood.

Purpose of the Study:

• To deeply phenotype 22 individuals with NR2F1 variants, focusing on neurodevelopmental and ophthalmological aspects.
• To investigate structural and functional changes in the retina and optic nerve.
• To explore the impact of NR2F1 variants on visual system development using a mouse model.

Main Methods:

• Deep phenotyping of 22 individuals with NR2F1 variants.
• High-resolution optical coherence tomography (OCT) and diffusion tensor imaging (DTI) tractography.
• Analysis of an Nr2f1 mutant mouse model.

Main Results:

• Individuals showed early-onset visual impairment, optic nerve hypoplasia, retinal ganglion cell loss, and thinning of the ganglion cell layer.
• No significant visual function deterioration was observed during follow-up.
• Mouse models exhibited abnormal retinogenesis, reduced retinal ganglion cell density, and disrupted axonal guidance, leading to optic nerve hypoplasia and reduced visual acuity.

Conclusions:

• NR2F1 pathogenic variants cause early neurodevelopmental defects in the retina and optic nerve, resulting in congenital, non-progressive vision loss.
• NR2F1 is crucial for orchestrating early retinal and optic nerve head development and visual system maturation.
• Findings support NR2F1 as a major gene in visual system development.