Investigating aniridia, a human genetic eye disorder
McDougal, Margaret Elizabeth
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Aniridia is a rare congenital eye disorder typically diagnosed postnatally by partial or full iris hypoplasia. Associated foveal hypoplasia, indicated by early infancy nystagmus, causes reduced visual acuity. The progressive nature of the disease frequently leads to multiple ocular abnormalities such as glaucoma, keratopathy, cataracts, corneal vascularization and corneal opacification. Two-thirds of aniridic patients have heterozygous mutations in the PAX6 gene. The PAX6 protein is a highly conserved transcription factor crucial for normal eye development and cornea homeostasis, however the proteins exact molecular mechanism is still uncertain. Understanding the phenotypic variation caused by different PAX6 mutations helps explain the molecular mechanism of the mutated protein and the complex role of PAX6 in the eye. In this project, we screened the PAX6 gene of 157 individuals, representing 58 aniridic families, by direct gene sequencing and conducted detailed ophthalmologic evaluations for each aniridic patient. A total of 38 mutations were identified, including 20 novel mutations. I compiled our results with the Human PAX6 Allelic Variant Database to create a total of 565 independently ascertained variants in PAX6. Of these variants, 525 are associated with ocular malformations and 459 are specifically causal for isolated aniridia. Further analysis of mutation type frequencies and distributions indicated that nonsense (39%), frame-shift (29%), and splice junction (18%) mutations are predominately associated with aniridia, whereas the majority of non-aniridia phenotypes are caused by missense mutations (76%). This compiled mutation spectrum continues to yield important insight into the molecular mechanism of the mutated protein and the likely phenotypic defects.