Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly

Abstract

Mutation or deletion of the PAX6 gene underlies many cases of aniridia. Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters' anomaly. First, a child with Peters' anomaly is deleted for one copy of PAX6. Second, affected members of a family with dominantly inherited anterior segment malformations, including Peters' anomaly are heterozygous for an R26G mutation in the PAX6 paired box. Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters' anomaly. We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations.

Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

“…In this paper, we analysed the mechanism of DNAbinding and transcriptional activation by Pax6, by using the paired domain mutants previously isolated from patients with ocular disorders (Hanson et al 1994;Azuma et al 1996). Extending previous observations (Epstein et al 1994b), we clearly demonstrate that the two subdomains can bind independently to their cognate sites.…”

“…Taken together, the R128C mutation that hyperactivates transcription directed from P6CON and abolishes the transactivation via 5aCON causes a defect of the posterior part of the eye (Azuma et al 1996), while the R26G mutation that reduces the transactivation via P6CON and hyperactivates the transcription directed from 5aCON is associated with a defect in the anterior part (Hanson et al 1994). Another point mutation that occurs in the exon 5a splice acceptor of PAX6 and increases the ratio of Pax6-5a variant has been reported which also causes a defect of the anterior part (Epstein et al 1994b).…”

The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic

“…Molecular genetic studies reveal that a number of mutations in genes controlling anterior segment development will result in the formation of PE and other abnormalities. 10,11 For example, defects in PITX2 and FOXC1 are associated with Axenfeld-Reiger syndrome and JAG1 with Alagille's syndrome. 2,[10][11][12] Axenfeld-Reiger syndrome is an autosomal dominant condition characterised by iris strands spanning the angle to insert into the prominent Schwalbes line.…”

“…10,11 For example, defects in PITX2 and FOXC1 are associated with Axenfeld-Reiger syndrome and JAG1 with Alagille's syndrome. 2,[10][11][12] Axenfeld-Reiger syndrome is an autosomal dominant condition characterised by iris strands spanning the angle to insert into the prominent Schwalbes line. 10 The PE while often extensive in this condition may only be visible with gonioscopy, or be limited as in the two cases in this study.…”

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

“…In Peters anomaly, there are reports identifying mutations in a number of genes, including PAX6, PITX2, FOXC1, MAF, FOXE3, PITX3 and CYP1B1. 1, 5,6 Overlap in clinical features is evident with some patients with mutations in a particular gene having cataract/microcornea while others may have a specific anterior segment dysgenesis phenotype, and microphthalmia may also be present. 7 As an example, mutations in the gene FOXE3 may be found in patients with cataract, disorders of the anterior segment and microphthalmia ( Figure 1).…”