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Article Dans Une Revue Brain Communications Année : 2021

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

Michele Bertacchi
  • Fonction : Auteur
Chiara Tocco
Ungsoo Samuel Kim
  • Fonction : Auteur
Adam Kruszewski
  • Fonction : Auteur
Robert Avery
  • Fonction : Auteur
Jinu Han
Sung Jun Ahn
  • Fonction : Auteur
Nikolas Pontikos
Indran Davagnanam
  • Fonction : Auteur
Marios Kaliakatsos
  • Fonction : Auteur
Alice Gardham
  • Fonction : Auteur
Ngozi Oluonye
  • Fonction : Auteur
Maddy Ashwin Reddy
  • Fonction : Auteur
Elaine Clark
  • Fonction : Auteur
Elisabeth Rosser
  • Fonction : Auteur
Patrizia Amati-Bonneau
  • Fonction : Auteur
Majida Charif
  • Fonction : Auteur
Isabelle Meunier
  • Fonction : Auteur
Sabine Defoort
  • Fonction : Auteur
Catherine Vincent-Delorme
  • Fonction : Auteur
Anthony Robson
  • Fonction : Auteur
Graham Holder
  • Fonction : Auteur
Luc Jeanjean
  • Fonction : Auteur
Antonio Martinez-Monseny
  • Fonction : Auteur
Mariona Vidal-Santacana
  • Fonction : Auteur
Chloé Dominici
  • Fonction : Auteur
Cedric Gaggioli
  • Fonction : Auteur
Nadia Giordano
  • Fonction : Auteur
Matteo Caleo
  • Fonction : Auteur
Grant Liu
  • Fonction : Auteur
Andrew Webster
  • Fonction : Auteur
Michèle Studer
Patrick Yu-Wai-Man
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-03861112 , version 1 (19-11-2022)

Identifiants

Citer

Neringa Jurkute, Michele Bertacchi, Gavin Arno, Chiara Tocco, Ungsoo Samuel Kim, et al.. Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model. Brain Communications, 2021, 3 (3), ⟨10.1093/braincomms/fcab162⟩. ⟨hal-03861112⟩
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