Purpose: Aniridia is caused by a mutation of the PAX6 gene. Haploinsufficiency of the gene product is thought to result in the aniridia phenotype, because most mutations thus far detected have been large deletions encompassing the entire gene and nonsense, frameshift, or splice errors that result in premature translational termination on one of the alleles. Only two missense mutations have been detected in aniridia pedigrees, each of which occurs in its paired domain or homeodomain. In this study, four novel missense mutations were found in three aniridia pedigrees.
Methods: Polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of the PAX6 gene were performed using genomic DNA of three aniridia pedigrees and more than 100 healthy control subjects.
Results: Three mutations occurred in the N-terminal subdomain of the paired domain, namely N17S, I29V, and R44Q, the first two of which were detected on the same allele of one patient. The other mutation (Q178H) was in the linking portion of the paired domain and homeodomain.
Conclusions: These missense mutations give rise to haploinsufficiency by another route, because the missense mutations presented here resulted in an aniridia phenotype indistinguishable from that caused by a heterozygous deletion of the entire PAX6 gene.