Abstract
Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch–Boonstra–Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.
Highlights
Inherited optic neuropathies are an important cause of visual impairment in young children with an estimated prevalence of 1 in 10 000.1 genetically heterogeneous with both nuclear and mitochondrial genes being implicated, the pathological hallmark is the marked vulnerability of retinal ganglion cells (RGCs) leading to optic nerve degeneration and irreversible visual loss.[2]
Pathogenic NR2F1 variants are clustered within the DNA-binding domain (DBD) and ligand-binding domain (LBD)
This study demonstrates that the optic neuropathy caused by pathogenic NR2F1 variants is of early neurodevelopmental origin, with limited evidence of progression in later life
Summary
Inherited optic neuropathies are an important cause of visual impairment in young children with an estimated prevalence of 1 in 10 000.1 genetically heterogeneous with both nuclear and mitochondrial genes being implicated, the pathological hallmark is the marked vulnerability of retinal ganglion cells (RGCs) leading to optic nerve degeneration and irreversible visual loss.[2] In autosomal dominant or recessive optic atrophy caused by pathogenic OPA1 (OMIM 605290) and WFS1 (OMIM 606201) variants, progressive RGC loss starts in early childhood and most patients are registered legally blind by the fifth decade of life.[3] High-resolution optical coherence tomography (OCT) imaging has made it possible to visualize and monitor the loss of RGCs, and in most inherited optic neuropathies, there is early loss of RGCs within the papillomacular bundle that becomes more generalized as the disease progresses.[1,4] Optic nerve hypoplasia (ONH) is a non-progressive congenital disease characterized by underdevelopment of the optic nerve that is often accompanied by other structural ocular abnormalities. The transcription factors implicated in ONH participate in the proper development of the optic stalk (OS) and optic nerve by directly participating in the intricate sequential steps coordinating ocular morphogenesis and maturation.[8]
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