PAX6 disease models for aniridia

Abstract

Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.

Novel variants in the PAX6 gene related to isolated aniridia

“…The nonsense variants were the most common in our group, which is consistent with the medical literature 16,17 . The frameshift (39% vs. 27%), missense (12%), splice site (15%), and small indels (2%) were observed less frequently 16,30 . According to medical literature, there are four variants that occur significantly more often than the others: p.R203*, p.R240*, p.R261*, and p.R317* 2 .…”

“…were observed less frequently. 16,30 According to medical literature, there are four variants that occur significantly more often than the others: p.R203*, p.R240*, p.R261*, and p.R317*. 2 Three of them were identified in our group, and p.R317* variant occurred twice.…”

“…However, according to some other studies, different nonsense mutations do not correlate with phenotypes in a statistically significant manner, although they all lead to the PAX6 protein haploinsufficiency 17,33 . In fact, according to the literature, the phenotype can differ extensively, even within the same family 30 …”

“…17,33 In fact, according to the literature, the phenotype can differ extensively, even within the same family. 30 The foveal hypoplasia and hyperopia were present in patients with variants located in the linker domain of the PAX6 gene (P4, P6, P9, and P10). Cataract and glaucoma occurred only in the adult P10.…”