The long and short‐‘sightedness’ of BMP3 in eye development

Purpose: Following genome‐wide association study for risk factors for retinal detachment, a locus overlapping the BMP3 gene, previously reported to be associated with myopia, was identified and selected for further examination. We prioritized an associated missense plausibly deleterious variant within the BMP3 gene for functional analysis. The BMP signalling pathway has long been implicated in the patterning and development of the eye, but BMP3's role both within this pathway and during eye development and disease is unclear. Methods: The region around the associated missense variant is conserved between human and mouse, and the missense variation was introduced using CRISPR‐cas9 genome editing; loss of function mutations were also produced in the process. Our unit is uniquely equipped to analyse mouse eye phenotypes and using Optical Coherence Tomography (OCT), electroretinogram (ERG) and Optokinetic Drum (OKD) these mice were comprehensively phenotyped through to adulthood. RNA sequencing analysis was also used in cell lines and in primary mouse tissue to further investigate disrupted signalling pathways and potential downstream targets of Bmp3. Results: OCT of mice showed no gross morphological abnormalities in either mice carrying the missense variant or loss of function mutations. ERG and OKD also showed that retinal function and visual acuity was unaltered in either line. However axial length measurements of adult mice showed a significant increase in length of the eye – indicative of myopia. Transcriptional analysis of two different retinal pigmented epithelial cell lines carrying loss of function mutations have been compared to results obtained from whole eye cups of mutant mice, and we have highlighted potential differences and similarities between the two. Conclusions: Future work is required to assess how much the mouse and human cell line results converge, but our mouse results support a role for a BMP pathway in myopia development.