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

Abstract

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed.

The Ocular Neural Crest: Specification, Migration, and Then What?

“…Pax6 gene mutations have also been linked to PA. Notably, mutations in Pax6 are more typically associated with aniridia, a panocular congenital disease characterized by foveal hypoplasia, optic nerve hypoplasia, limbal stem cell deficiency, and varying degrees of iris hypoplasia (reviewed in Lim et al, 2017 ; Sannan et al, 2017 ; Syrimis et al, 2018 ; Wawrocka and Krawczynski, 2018 ; Lima Cunha et al, 2019 ; Lee et al, 2020 ; Tripathy and Salini, 2020 ). However, phenotypic variation of the same Pax6 gene mutation has shown both aniridia and PA within one family ( Wang et al, 2018 ), and PA has been associated with aniridia in more than 10% of cases ( Dolezal et al, 2019 ).…”

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

“…Aniridia associated with mutations in PAX6 was categorized into classic aniridia group, while that associated with mutations in genes other than PAX6 was aniridia-like group [7,8]. Classic aniridia referred to a pan-ocular disorder, including partial or near total absence of iris, cataract, aniridia-associated keratopathy (ARK), glaucoma, foveal hypoplasia, optic disk hypoplasia and nystagmus [14][15][16]. Iris hypoplasia was the most important feature of aniridia, which could range from complete absence of the iris, through enlargement and irregularity of the pupil mimicking a coloboma, to small slit-like defects in the anterior layer seen only on transillumination with a slit-lamp.…”

“…The human PAX6 gene produced 2 alternatively spliced isoforms that have the distinct structure of the paired domain [20]. There have been about 500 mutations reported in the human PAX6 database [14] (https://www.ncbi.nlm.nih.gov/clinvar?term=607108[MIM]), since rstly identi ed as the genetic cause of aniridia in the small eye mouse [21]. While it was remarkable that the alterations in a conserved non-coding element within the "critical region" and other cis-regulatory elements also could cause aniridia [22].…”

Practical guide to genetic screening for inherited eye diseases

“… 30 – 32 PAX6 variants can cause aniridia, which affects 1:40,000–100,000 births, leading to a variable degree of iris and foveal hypoplasia, nystagmus, cataract, glaucoma and corneal keratopathy. 33 , 34…”