3′ deletions cause aniridia by preventing PAX6 gene expression

Abstract

Aniridia is a panocular human eye malformation caused by heterozygous null mutations within PAX6, a paired-box transcription factor, or cytogenetic deletions of chromosome 11p13 that encompass PAX6. Chromosomal rearrangements also have been described that disrupt 11p13 but spare the PAX6 transcription unit in two families with aniridia. These presumably cause a loss of gene expression, by removing positive cis regulatory elements or juxtaposing negative DNA sequences. We report two submicroscopic de novo deletions of 11p13 that cause aniridia but are located >11 kb from the 3 end of PAX6. The clinical manifestations are indistinguishable from cases with chain-terminating mutations in the coding region. Using human ؋ mouse retinoblastoma somatic cell hybrids, we show that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Our findings suggest that remote 3 regulatory elements are required for initiation of PAX6 expression.

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

“…Misexpression of genes due to changes in their regulatory landscape is becoming associated with a growing number of human disorders (Lauderdale et al. 2000; Volkmann et al. 2011; Spielmann et al.…”

“…Copy number variation analysis was instrumental to the discoveries of regulatory regions/mutations associated with disease phenotypes (Lauderdale et al. 2000; Volkmann et al. 2011).…”

Continuous expression of the homeobox gene Pax6 in the ageing human retina

“…These disorders range from autosomal dominant keratitis, congenital cataract, Peter's anomaly and aniridia to isolated foveal hypoplasia, [3][4][5][6][7][8][9][10][11] for review see. 14 Furthermore, homozygous human Pax6 mutations lead to anophtalmia, brain malformation, and early postnatal Figure 1 Western blot analysis of PAX6 expression and its alternative splice forms in human retinas at various ages (17,28,36,45,55,66, and 79 years).…”

“…In the last years, a number of human Pax6 mutations have been identified leading to a variety of ocular malformations of the anterior and posterior segment. [3][4][5][6][7][8][9][10][11] In the developing human retina, PAX6 expression can be histochemically detected in the Inner Nuclear Layer and Ganglion Cell Layer, as demonstrated by Nishina et al 12 in human foetuses up to gestation week 22.…”

Neurogenesis in the Fish Retina

“…In vertebrates, pax6 genes are expressed in eye primordia , and this expression persists through the early stages of retinal neurogenesis when pax6 is downregulated in all retinal cell types except ganglion cells and amacrine cells (Hitchcock et al, 1996). Overexpression of pax6 in vertebrates results in the formation of ectopic eye tissue (though not whole eyes [Chow et al, 1999]), and disruption of pax6 expression results in eye abnormalities (Lauderdale et al, 2000). In the zebrafish, a transition zone defined by the proximal limit of pax6 expression defines tissues of the future eye (retina and retinal pigmented epithelium) as distinct from the optic stalk and more proximal structures, which express a related factor, pax2 (Macdonald et al, 1995).…”