Genetic Disorders of Vision Revealed by a Behavioral Screen of 400 Essential Loci in Zebrafish

TLDR

These zebrafish strains harbor single point mutations in over 400 essential loci. The study aimed to determine what proportion of these mutants exhibit blindness or other visual system impairments. The authors screened 450 zebrafish mutants for optokinetic and optomotor responses, using behavioral assays to identify visual deficits. Twelve mutants lacked optokinetic or optomotor responses, and detailed analyses uncovered diverse visual pathway defects—including lens degeneration, melanin loss, ganglion cell absence, axon misrouting, optic nerve disorganization, inner nuclear/outer plexiform layer dysfunction, and retinotectal activity disruption—while 13 blind mutants exhibited outer‑retina dystrophy, making it the most common inherited blindness in zebrafish; overall, ~5% of essential loci affect vision without systematic morphological linkage.

Abstract

We examined optokinetic and optomotor responses of 450 zebrafish mutants, which were isolated previously based on defects in organ formation, tissue patterning, pigmentation, axon guidance, or other visible phenotypes. These strains carry single point mutations in >400 essential loci. We asked which fraction of the mutants develop blindness or other types of impairments specific to the visual system. Twelve mutants failed to respond in either one or both of our assays. Subsequent histological and electroretinographic analysis revealed unique deficits at various stages of the visual pathway, including lens degeneration ( bumper ), melanin deficiency ( sandy ), lack of ganglion cells ( lakritz ), ipsilateral misrouting of axons ( belladonna ), optic-nerve disorganization ( grumpy and sleepy ), inner nuclear layer or outer plexiform layer malfunction ( noir , dropje , and possibly steifftier ), and disruption of retinotectal impulse activity ( macho and blumenkohl ). Surprisingly, mutants with abnormally large or small eyes or severe wiring defects frequently exhibit no discernible behavioral deficits. In addition, we identified 13 blind mutants that display outer-retina dystrophy, making this syndrome the single-most common cause of inherited blindness in zebrafish. Our screen showed that a significant fraction (∼5%) of the essential loci also participate in visual functions but did not reveal any systematic genetic linkage to particular morphological traits. The mutations uncovered by our behavioral assays provide distinct entry points for the study of visual pathways and set the stage for a genetic dissection of vertebrate vision.