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Abstract
The paired-box 6 (PAX6) gene encodes a highly conserved transcription factor that is essential for proper development of the eye and brain. Heterozygous loss-of-function mutations in PAX6 are causal for a condition known as aniridia in humans and the Small eye phenotype in mice. Aniridia is a predominantly characterized by iris hypoplasia and other ocular abnormalities, but recent evidence of neuroanatomical, sensory, and cognitive impairments in this population has emerged, indicating brain-related phenotypes as a prevalent feature of the disorder. Determining the neurophysiological origins of brain-related phenotypes in this disorder presents a substantial test, as the majority of extra-ocular traits in aniridia demonstrate a high degree of heterogeneity. Similarly, the molecular mutations of PAX6 that are causal for aniridia are highly variable. These challenges demonstrate that a single line of investigation is insufficient for understanding aniridia as a whole. The work presented here implemented three approaches towards an integrative understanding of this condition: (i) molecular genetic analysis of human PAX6 mutations to investigate the spectrum of molecular changes associated with the disorder, (ii) structural magnetic resonance imaging (MRI) of a rodent model of aniridia to determine the neuroanatomical consequences of PAX6 mutations which are conserved across species and attributable to PAX6 deficiency, and (iii) an auditory paradigm administered to humans with aniridia and measured by electroencephalography (EEG) to examine the fine temporal and spectral dynamics of auditory processing dysfunction in this disorder. Together, these experiments contribute to our understanding of aniridia from molecular, anatomical, and functional perspectives, and provide a framework for investigating the link from genetic mutations to complex neural abnormalities.