PAX6 Mutational Status Determines Aniridia-Associated Keratopathy Phenotype

Abstract

Congenital aniridia (Online Mendelian Inheritance in Man identifier, 106210) is a rare, severely visually impairing disease caused principally by heterozygous mutation in the paired box 6 (PAX6) gene that orchestrates normal ocular development. 1 The disease results in underdevelopment or abnormal development of eye structures including the cornea, leading to a bilateral and progressive limbal stem cell insufficiency and conjunctivalization of the cornea called aniridia-associated keratopathy (AAK). However, clinical manifestation of AAK, rate of progression, and prognosis can vary widely across individuals, precluding the development of general guidelines for treatment. Congenital aniridia can result from any of more than 400 unique mutations in the PAX6 gene that may lead to a spectrum of clinical phenotypes. 2 Aniridia-associated keratopathy phenotype can vary from a fully transparent cornea to a thick, opaque, vascularized pannus at any stage of life. As clinical genetic analysis becomes more sophisticated and widespread, the clinical consequence of various PAX6 mutations requires more detailed attention. However, to date, genotypeephenotype studies in aniridia describe the entire eye, 3,4 providing only general assessment of corneal opacity. Accordingly, we performed detailed clinical characterization of AAK phenotype across a range of ages and in parallel documented PAX6 mutational status to determine how genotype influences the clinical phenotype of AAK. Adult and pediatric patients with clinically diagnosed congenital aniridia included in a patient registry maintained at

PAX6 Genotypic and Retinal Phenotypic Characterization in Congenital Aniridia

“…Multiple exon deletions have previously been reported to result in a more severe corneal phenotype. 46 The same was observed here as four of seven participants with large PAX6 deletions had corneal opacities that precluded retinal imaging. The three who were imaged (5134, 5154, 5117) had retinal phenotypes ranging from mild to severe (foveal hypoplasia [FH] grades 1–4).…”

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

“…Accordingly, a recent report from Pedersen et al showed that family members with the same PAX6 mutation, a 2 bp deletion in intron 2, presented with variable iris involvement, which ranged from almost normal to no iris, as well as different degrees of foveal hypoplasia [115,116]. In contrast, Lagali et al recently found a correlation between PAX6 variants and the severity and progression of ARK [117,118]. In a cohort of 46 aniridia patients, the authors found a minimal level of keratopathy and an increase in cornea thickness in all aniridia patients from early age.…”

“…Patients with whole gene deletions presented the most severe and early onset ARK, followed by those with PTC or CTE mutations. Patients with missense mutations showed milder non-progressive ARK and, lastly, non-PAX6 mutations had the mildest forms of disease and generally the best visual acuity [118]. However, the clinical phenotype of ARK is heterogenous and patients with the same mutation can often display different degrees of ARK.…”

A novel variant in PAX6 as the cause of aniridia in a Chinese family

“…A high proportion of cases of aniridia was associated with mutations in PAX6 frameshift mutations, splicing site mutations or nonsense mutations and these kinds of variations have been considered to produce premature truncation of the protein or nonsense transcripts, leading to haploinsu ciency. While few cases were caused by missense mutations [16]. Aniridia phenotype associated with PAX6 haploinsu ciency almost present anterior segment and fundus abnormalities, while missense mutations in PAX6 were mostly associated with dysplasia of skeleton and central nervous system [18].…”