Pathogenic <i>NR2F1</i> variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.
Creators: name: Jurkute, Neringa
name: Bertacchi, Michele
name: Arno, Gavin
name: Tocco, Chiara
name: Kim, Ungsoo Samuel
name: Kruszewski, Adam M
name: Avery, Robert A
name: Bedoukian, Emma C
name: Han, Jinu
name: Ahn, Sung Jun
name: Pontikos, Nikolas
name: Acheson, James
name: Davagnanam, Indran
name: Bowman, Richard
name: Kaliakatsos, Marios
name: Gardham, Alice
name: Wakeling, Emma
name: Oluonye, Ngozi
name: Reddy, Maddy Ashwin
name: Clark, Elaine
name: Rosser, Elisabeth
name: Amati-Bonneau, Patrizia
name: Charif, Majida
name: Lenaers, Guy
name: Meunier, Isabelle
name: Defoort, Sabine
name: Vincent-Delorme, Catherine
name: Robson, Anthony G
name: Holder, Graham E
name: Jeanjean, Luc
name: Martinez-Monseny, Antonio
name: Vidal-Santacana, Mariona
name: Dominici, Chloé
name: Gaggioli, Cedric
name: Giordano, Nadia
name: Caleo, Matteo
name: Liu, Grant T
name: Webster, Andrew R
name: Studer, Michèle
name: Yu-Wai-Man, Patrick
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Mouse Model
Nr2f1
Bbsoas
Inherited Optic Neuropathy
Optic Nerve Head Anomalies

description: Funder: National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology
description: Pathogenic <i>NR2F1</i> 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 <i>NR2F1</i> 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 <i>NR2F1</i> variants impact on retinal and optic nerve development, we took advantage of an <i>Nr2f1</i> mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in <i>Nr2f1</i> 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 <i>NR2F1</i> pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose <i>NR2F1</i> as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.