The Function of KIAA0319 in Human Neuronal Development

Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Gruen, Jeffrey

Abstract

Reading Disability (RD), also known as dyslexia, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of RD is between 5% and 17%, and the heritability ranges from 44% to 75%. Genetic linkage analysis and genome-wide association studies (GWAS) have identified several genes and regulatory elements linked to RD and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. Association of KIAA0319 has been independently replicated in multiple independent studies and languages. Rodent models suggest that KIAA0319 is involved in neuronal migration, but its precise function is unknown. These studies aim to determine the mechanisms by which KIAA0319 affects reading and language performance. We hypothesize that KIAA0319 plays a critical role in neuronal development. My thesis aims to study these effects and to relate them to brain development, focusing on the pathways potentially involved in reading performance. We present a study showing an inducible knockdown of KIAA0319 which suggests a role in the early stages of neurogenesis. We then use a constitutive knockdown of KIAA0319 to show regulatory effects on neuronal progenitor cells, implying effects on proliferation and differentiation. These studies show a potential connection between dyslexia-associated genes and brain development.

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