Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

Abstract

Background Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis. Results We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

Unique Haplotypes in OPN1LW as a Common Cause of High Myopia With or Without Protanopia: A Potential Window Into Myopic Mechanism

“…Decreased levels of arrestin encoded by ARR3 , functioning as the desensitizer of opsins, result in increased activity of L and M cones and enhanced sensitivity of color vision signals, which has been proposed to explain the onset of high myopia secondary to heterozygous variants in ARR3 . 52 It was hypothesized that the mosaic cone status with adjacent cones expressing different functional opsins of affected female patients with heterozygous variants in ARR3 is similar to that of affected male patients with hemizygous LVAVA in OPN1LW with a partial effect on splicing. The relationship between OPN1LW and ARR3 was similar to that between RHO and SAG , in which RHO , which encodes rhodopsin, was activated when retinal was isomerized from the 11-cis to the all-trans configuration, and its inactivation could be prevented by binding to the arrestin encoded by SAG .…”

Whole exome sequencing of known eye genes reveals genetic causes for high myopia

“…An extensive description of the families is described elsewhere ( 24 ). Up to now, there were only very few reports on patients with mutations in this gene ( 21 , 25–27 ). Pathogenic variants in ARR3 are associated with a specific female-limited inheritance pattern of high myopia, caused by the cellular inference between the active and inactivated X-chromosome present in females ( 21 ).…”

“…Pathogenic variants in ARR3 are associated with a specific female-limited inheritance pattern of high myopia, caused by the cellular inference between the active and inactivated X-chromosome present in females ( 21 ). The exact role of the cone Arrestin 3 protein in the visual signaling cascade is not known, but an effect on circadian rhythm, dopamine release, blue light and melanopsin has been proposed ( 25 ). In a bovine animal model, the location of this protein varied depending on the light conditions, i.e.…”

Pathogenic variant in the X‐linked ARR3 gene associated with variable early‐onset myopia

“…In these two reported families all heterozygous females had eoHM, while confirmed and presumed hemizygous males were unaffected (Liu et al, 2020). A separate group also identified another variant (c.214C>T, p.Arg72*) in the ARR3 gene in the first described European family; all with isolated eoHM (Széll et al, 2021).…”