Not too long, not too short: Goldilocks principle of eye size

Abstract

For most of the world, normal vision and visual acuity are central to our lives and livelihoods. Abnormal vision is often equated with conditions such as cataracts or retinal degeneration, but increasingly recognized contributors to abnormal vision are serious disturbances in visual acuity caused by uncorrected refractive error. In 2017, the Vision Loss Expert Group projected that uncorrected refractive error will become a major cause of global vision impairment and blindness by 2020 [1]. Although refractive error such as nearsightedness (myopia) and farsightedness (hyperopia) is usually correctable with eyeglasses, high myopia and high hyperopia can result in significant vision loss, and even irreversible blindness, due to complications such as macular degeneration and glaucoma. Myopic macular degeneration gives rise to similar outcomes as does age-related macular degeneration, with a notable difference-the former affects patients of much younger age. At the other end of the refractive spectrum, high hyperopia commonly leads to angle closure glaucoma. Furthermore, extremely high hyperopia associated with nanophthalmos-a small eye caused by developmental abnormalities-almost always leads to angle closure glaucoma, for which surgical correction is challenging and often associated with severe complications [2]. Understanding the pathogenesis of refractive error is greatly needed to develop effective treatments. High myopia or hyperopia is commonly caused by lengthening or shortening of axial length (AL) of the eye, respectively. If AL is too long, the sclera (the white outer layer of the eye) becomes stretched and thinned, predisposing to retinal detachment and degeneration of the retinal pigment epithelium. Conversely, if AL is too short, internal eye structures are crowded, and the sclera becomes thickened, predisposing to angle closure glaucoma and choroidal effusion. Recent studies in PLOS Genetics provide new insight into the genes and gene interactions, that contribute to abnormalities in axial length and refraction, and, furthermore, represent an intersection between common and rare genetic disease. On the common side of the spectrum, myopia and hyperopia have been the subject of several genome wide association studies (GWAS). TMEM98, which encodes a widely expressed single transmembrane protein of unknown function [3,4], is one of several loci associated with high myopia in GWAS, but a definitive and mechanistic role for TMEM98 in axial length has not been apparent from GWAS. On the rare side of the spectrum, however, deleterious coding alterations in TMEM98 co-segregate with autosomal dominant nanophthalmos in large multigenerational families [5,6]. Intriguingly, nanophthalmos is the phenotypic opposite of high myopia, a paradox that is underscored by a report of 3 variants in TMEM98 associated with high myopia in Chinese patients [7].