The PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the PAX6 gene cause aniridia (absence of the iris) and related developmental eye diseases. PAX6 mutations are archived in the Human PAX6 Allelic Variant Database, which currently contains 309 records, 286 of which are mutations in patients with eye malformations.

We examined the records in the Human PAX6 Allelic Variant Database and documented the frequency of different mutation types, the phenotypes associated with different mutation types, the contribution of CpG transitions to the PAX6 mutation spectrum, and the distribution of chain-terminating mutations in the open reading frame. Mutations that introduce a premature termination codon into the open reading frame are predominantly associated with aniridia; in contrast, non-aniridia phenotypes are typically associated with missense mutations. Four CpG dinucleotides in exons 8, 9, 10 and 11 are major mutation hotspots, and transitions at these CpG's account for over half of all nonsense mutations in the database. Truncating mutations are distributed throughout the PAX6 coding region, except for the last half of exon 12 and the coding part of exon 13, where they are completely absent. The absence of truncating mutations in the 3' part of the coding region is statistically significant and is consistent with the idea that nonsense-mediated decay acts on PAX6 mutant alleles.

The PAX6 Allelic Variant Database is a valuable resource for studying genotype-phenotype correlations. The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles.