Pax6 3' deletion results in aniridia, autism and mental retardation

Abstract

The PAX6 gene is a transcription factor expressed early in development, predominantly in the eye, brain and gut. It is well known that mutations in PAX6 may result in aniridia, Peter's anomaly and kertatisis. Here, we present mutation analysis of a patient with aniridia, autism and mental retardation. We identified and characterized a 1.3 Mb deletion that disrupts PAX6 transcriptional activity and deletes additional genes expressed in the brain. Our findings provide continued evidence for the role of PAX6 in neural phenotypes associated with aniridia.

Fig. 1

Pedigree of family A

Fig. 2

Deletion region in patient 3A. The deletion is 1.3 MB and contains enhancer elements (“e”) for PAX6, as well as a number of other potential autism candidate genes. The dots in the upper part of the ideogram indicated individual signal intensity values for SNP probes, the line within the dots is a Hidden Markov Model prediction of copy number. The lower part of the CNAG ideogram is a smoothed statistical average of signal intensity. The CNAG output is scaled to the chromosome key below it, indicating the chromosome band of the deletion

Fig. 3

Deletion breakpoints in relation to some defined 3′ enhancer regions. Arrowheads represent patient deletion/rearrangement breakpoints. It should be noted that Crolla and van Heyningen (2002) identified more breakpoints than those depicted here, however this is the most proximal breakpoint that may leave PAX6 transcription unit in tact. Six children shared this breakpoint and all were under the age of 1 year when studied. The boxes represent enhancer regions (Griffin et al. 2002; Kleinjan et al. 2001, 2004, 2006; Kim and Lauderdale 2006). The downstream regulatory region is denoted with a dashed line. This region is critical to basal levels of PAX6 transcription. ELP4, which is not shown, is located approximately 27 Kb telomeric to PAX6