Summary
A bioRxiv preprint links NR2F1-related changes in retinoic-acid signalling in mouse retinas with foveal abnormalities seen on OCT in people with BBSOAS. The findings point to a retinal component of the syndrome’s visual pathology.
A bioRxiv preprint reports that disrupting the gene NR2F1 alters retinoic-acid signalling and the distribution of cone photoreceptors in mouse retinas. The researchers also describe foveal abnormalities on high-resolution optical coherence tomography (OCT) scans of people with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a genetic condition caused by pathogenic NR2F1 variants and associated with visual impairment.
The authors propose that these findings connect an NR2F1-controlled developmental network to human foveal specialization. The evidence comes from two different settings: molecular and cellular experiments in mice, and structural retinal imaging in people with BBSOAS. The report is a preprint and has not yet completed peer review.
NR2F1 and retinoic-acid signalling in mouse retinas
The team used single-cell RNA sequencing across three complementary mouse models of Nr2f1 disruption, including two carrying mutations based on variants found in patients. Across the models, they identified a shared gene-expression programme enriched for genes in the retinoic-acid (RA) pathway.
RA is a signalling molecule involved in development. Its effects depend in part on where it is available in a tissue. The researchers found that loss or mutation of Nr2f1 disrupted the spatial pattern of this signalling: expression of Cyp26a1, a gene that helps break down RA, extended from its usual dorso-equatorial region into the ventral retina. At the same time, the ventral-retina determinant Vax2 was reduced.
These molecular changes were associated with altered distributions of retinal cone photoreceptors expressing S- and M-opsin, light-sensitive proteins used in different parts of the visual spectrum. The study also reports that human NR2F1 binds a conserved regulatory region upstream of CYP26A1, supporting a direct role for NR2F1 in regulating local RA availability.
Together, the mouse results describe a pathway through which NR2F1 can influence the regional identity of the developing retina. They do not by themselves explain how that pathway produces a fovea: mice do not have the specialized foveal structure found in humans.
OCT findings in people with BBSOAS
In people with BBSOAS, high-resolution OCT revealed a smaller and shallower foveal pit, alongside increased retinal thickness at the centre of the retina. The authors describe this pattern as consistent with foveal hypoplasia, meaning incomplete development of the fovea, the retinal region important for sharp central vision.
The imaging provides evidence of a retinal structural feature in BBSOAS, complementing the syndrome’s known visual impairment. Read alongside the mouse experiments, it supports the possibility that NR2F1-related visual problems involve retinal development as well as other parts of the visual system. The human OCT findings are structural observations; the proposed NR2F1–RA–CYP26A1 mechanism was investigated in the experimental models, not directly measured in patients.