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K. Linkroum, E. A. DelBono, J. L. Wiggs; A Novel Pax6 In-Frame Insertion in the Paired Domain is Associated With a Severe Ocular Phenotype. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3071.
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Heterozygous mutations of the PAX6 gene cause a number of ocular abnormalities, including aniridia, corneal anomalies (Peter’s), cataract, glaucoma, nystagmus and foveal hypoplasia. As part of a screen of 50 patients with anterior segment dysgenesis and glaucoma we identified a patient with a novel 3 base pair insertion in the PAX6 gene. The purpose of this study was to determine the effect of the mutation on the PAX6 protein and characterize the phenotype of affected members of the pedigree.
After IRB approval, medical records for all members of the affected pedigree were obtained. Genomic DNA was purified from mouthwash samples and all PAX6 exons and flanking intron sequence were directly sequenced using the ABI3100 sequence analyzer and BIGDYE chemistries. Sequence analysis was done using the contig alignment function of Vector NTI. The normal and mutant PAX6 paired box domains were modeled using the Scratch Protein Predictor program (scratch.proteomics.ics.uci.edu).
The proband, her sister, mother and maternal grandmother were all diagnosed with early onset cataracts (by age 3) and glaucoma. The proband and her sister were available for more detailed exam and were both found to have horizontal nystagmus, small optic nerves and probable foveal hypoplasia. In both sisters the iris was formed but the pupil was irregular and functioned poorly. DNA sequencing of the PAX6 gene revealed a 3 base pair DNA insertion in all affected family members, causing a single aspartate amino acid insertion between tyrosine residues 61 and 62 in the DNA binding region of the paired box domain (Y61insD). Protein modeling showed that the insertion of the aspartate residue decreased the hydophobicity, and increased the charge of the DNA binding site.
The most common PAX6 mutations are premature termination mutations, amino acid substitutions, and C-terminal extensions. Mutations that inactivate one copy of the gene typically cause a severe phenotype including foveal hypoplasia, marked iris anomalies, and severe visual impairment. Missense mutations in PAX6 affect invariant amino acids in the paired domain and have been associated with a milder phenotype. In this study we have identified a novel amino acid insertion (Y61insD) occurring at a DNA binding site in the paired domain. To our knowledge this is the first report of an in-frame insertion in the PAX6 gene. Individuals carrying this mutation have a severe phenotype including foveal hypoplasia and nystagmus suggesting that the insertion of a charged amino acid at this position in the paired box domain significantly reduces the function of the PAX6 protein.
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