The genetics of aniridia — simple things become complicated

Abstract

Aniridia is a rare, panocular disorder characterized by a variable degree of hypoplasia or the absence of iris tissue associated with additional ocular abnormalities. It is inherited in an autosomal dominant manner, with high penetrance and variable expression even within the same family. In most cases the disease is caused by haploinsufficiency truncating mutations in the PAX6 gene; however, in up to 30% of aniridia patients, disease results from chromosomal rearrangements at the 11p13 region. The aim of this review is to present the clinical and genetic aspects of the disease. Furthermore, we present a molecular diagnostic strategy in the aniridia patients. Recent improvement in the genetic diagnostic approach will precisely diagnosis aniridia patients, which is essential especially for children with aniridia in order to determine the risk of developing a Wilms tumor or neurodevelopmental disorder. Finally, based on the previous studies we describe the current knowledge and latest research findings in the topic of pathogenesis of aniridia and possible future treatment.

Causes and effects of haploinsufficiency

“…Paired‐box protein 6 ( PAX6 ) is a well‐known TF involved in several developmental pathways, with HI most clearly seen in the development of the eye (Wang, Shan, & Gregory‐Evans, ). Indeed, heterozygous LOF mutation in PAX6 results in aniridia, which is the absence of the iris (Wawrocka & Krawczynski, ). PAX6 expression in this tissue shows how a threshold effect can convert a 50% difference in gene dosage into a nearly 100% difference in protein dosage (Bhatia et al ., ).…”

“…If PAX6 protein levels are below the required concentration when eye development begins, then the positive‐feedback loop is not triggered, and expression of PAX6 rapidly disappears (Bhatia et al ., ). This feedback amplification, necessary for development of the iris, is not known to occur for PAX6 in other tissues where it is expressed, which may explain the tissue‐specific phenotype of aniridia (Bhatia et al ., ; Wawrocka & Krawczynski, ). In a mouse model, tissue‐specific suppression of PAX6 nonsense mutations, which restored its expression, was shown to rescue several aspects of eye function, even when applied after birth (Gregory‐Evans et al ., ; Wang et al ., ).…”

Impaired DNA-binding affinity of novel PAX6 mutations

“…The PAX6 gene (MIM 607108) is a highly conserved gene to play an essential role in eye development 1,2 . It was identified as a candidate gene for congenital aniridia by positional cloning, and acts as a "master control" gene for normal oculogenesis by encoding a transcriptional regulatory protein 2,3 .…”

“…The PAX6 gene (MIM 607108) is a highly conserved gene to play an essential role in eye development 1,2 . It was identified as a candidate gene for congenital aniridia by positional cloning, and acts as a "master control" gene for normal oculogenesis by encoding a transcriptional regulatory protein 2,3 . The protein has two DNA-binding domains, a paired domain (PD) and a homeodomain, that recognize different DNA-binding sequences of target genes [4][5][6][7][8] .…”

“…To date, more than 400 heterozygous mutations within the PAX6 gene have been identified in the Human PAX6 Allelic Variant Database 2,[9][10][11] . Classically, PAX6 mutation is associated with an aniridia, but may also causes a variety of non-aniridia phenotypes such as microcornea, foveal hypoplasia, keratitis, and optic nerve malformations [12][13][14][15][16][17][18][19] .…”