The Aey80 mutation in the Pax 6 gene causes an age-dependent aniridia phenotype

Abstract

Purpose : Congenital aniridia is a rare condition resulting in vision impairment, characterized by incomplete development and abnormal formation of the eye, involving different degrees of iris, fovea, and optic nerve underdevelopment. Affected individuals experience reduced visual acuity and increased light sensitivity, with progressive deterioration due to corneal keratopathy, glaucoma, and associated manifestations, often leading to early adulthood blindness. The etiology of aniridia is linked to over 600 heterozygous pathogenic variations of the transcription factor paired box 6 (Pax6), a pivotal regulator of ocular development that exhibits dosage sensitivity in the eye. This study aims to delineate the characteristics of the Aey80 mutant, which presents a novel Pax6 allele.

Methods : Heterozygous Aey80 mice aged 7, 10, 26, and 40 weeks were evaluated for ocular characterization, comparing them to age-matched controls. Optical coherence tomography (OCT) assessed corneal thickness and structural abnormalities including iris length and anterior chamber depth. Invasion of blood- and lymphatic vessels was investigated using immunofluorescence staining with anti-CD31 and anti-Lyve1. Intraocular pressure (IOP) was measured by applanation tonometry.

Results : The Aey80 mutant mice exhibit aniridia markers: significantly reduced iris length and anterior chamber depth. In addition, whole-mount staining showed a massive ingrowth of LYVE-1⁺ lymphatic vessels, with less pronounced blood vessel ingrowth. Age-dependent alterations in corneal thickness were observed, showing various characteristics in 10-40-week-old mice compared to controls. Further, IOP is significantly increased in aging mice.

Conclusions : The Aey80 mutation results in an age-dependent aniridia-like phenotype, characterized by reduced iris and reduced anterior chamber dimensions. It induces shifts in corneal thickness and a substantial ingrowth of lymphatic vessels into the cornea, accompanied by increased intraocular pressure. These findings demonstrate the pivotal role of Pax6 in maintaining ocular structural integrity and functionality across different developmental stages. The Aey80 mouse model offers valuable insights into aniridia pathogenesis and allows for new treatment strategy development.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.