Disease relevance of Aniridia

• The relationship between genetic alterations at chromosomal band 11p13 and the WAGR (Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome is not clearly understood [1].
• To study this dosage effect, we characterized two PAX6 mutations in a family segregating aniridia and a milder syndrome consisting of congenital cataracts and late onset corneal dystrophy [2].
• Retinoblastoma is often inherited and accompanied by a deletion of chromosome 13 (band q14), while WT is occasionally associated with aniridia and deletion of chromosome 11 band p13 [3].
• Such mutations have been shown previously to be the cause of mouse developmental mutants (undulated, Splotch, and Small eye) and human syndromes (Waardenburg's syndrome and aniridia) and may thus differentially affect the regulation of target genes by the mutated Pax protein [4].
• Fluorescence in situ hybridization (FISH) with biotin-labeled probes mapping to 11p13 has been used for the molecular analysis of deletions of the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) locus [5].

Psychiatry related information on Aniridia

• Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies [6].

High impact information on Aniridia

• Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye [6].
• A candidate aniridia gene, AN, which is the human homologue of the mouse Pax-6 gene, has recently been isolated by positional cloning from the WAGR region of 11p13 [7].
• These findings indicate that the human aniridia and murine Small eye phenotypes arise from homologous defects in PAX6 [8].
• The mouse mutation Small eye (Sey), which has been proposed as a model for aniridia, results from defects in Pax-6, a gene containing paired-box and homeobox motifs that is specifically expressed in the developing eye and brain [8].
• Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region [9].

Chemical compound and disease context of Aniridia

• PAX6 mutation as a genetic factor common to aniridia and glucose intolerance [10].
• A case of human aniridia, where arginine 208 of LKRKLQR is mutated into a tryptophan, has been reported recently [11].
• BACKGROUND: Silicone keratopathy frequently develops as a complication of silicone oil tamponade in the management of severe trauma in eyes with partial or complete aniridia [12].

Biological context of Aniridia

• Upon examining the DNA samples of aniridia patients, we identified three missense mutations in the PST domain: P375Q (a novel mutation) and the previously reported Q422R and X423L mutations [13].
• However, aniridia cases with chromosomal rearrangements far downstream of an intact PAX6 gene suggested a requirement for additional cis-acting control for correct gene expression [14].
• In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations [10].
• However, several truncation mutations have been found to occur in the C-terminal half of PAX6 in patients with Aniridia resulting in mutant proteins that retain the DNA-binding domains but have lost most of the transactivation domain [15].
• These studies show that a combined conventional and molecular cytogenetic approach to patients presenting with aniridia is a useful method for differentiating between those with deletions extending into and including WT1 and therefore between those with high and low risks of developing Wilms' tumour [16].

Anatomical context of Aniridia

• For example, children with the rare paediatric syndrome AGR triad (aniridia, genito-urinary abnormalities and mental retardation) often develop Wilms' tumours at a very early age and carry a germ-line deletion on the short arm of chromosome 11 (11p13) [17].
• Because of the proximity of the two gene loci, assays of erythrocyte CAT may be useful to identify a submicroscopic deletion in some patients with sporadic aniridia and to predict a risk of developing Wilms tumor [18].
• By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-p14, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation) [19].
• PAX6 is also involved in the development of the endocrine pancreas, and reported to be a genetic factor common to aniridia and glucose intolerance, although the latter is usually mild [20].
• Host-cell reactivation (HCR) of UV-C-irradiated herpes simplex virus type 1 (HSV-1) has been determined in skin fibroblasts from the following hereditary cancer-prone syndromes: aniridia (AN), dysplastic nevus syndrome (DNS), Von Hippel-Lindau syndrome (VHL), Li-Fraumeni syndrome (LFS) and a family with high incidence of breast and ovarian cancer [21].

Gene context of Aniridia

• All observed mutations support the notion that haploinsufficiency in PAX6 results in aniridia and associated eye anomalies [22].
• Mutations in Pax6 function result in eye malformations known as Aniridia in humans and Small eye syndrome in mice [23].
• Mutations in a related gene, Pax-6, which, like Pax-3, has both a paired box and a paired-type homeobox sequence, cause the Small-eye mutation in mice and aniridia in man [24].
• We have detected a submicroscopic 11p13 deletion in a child with inherited aniridia who subsequently presented with Wilms tumor in a horseshoe kidney, only revealed at surgery [5].
• The possible role of PAXNEB in aniridia was assessed [25].

References