Date of Award
Open Access Thesis
Medical Doctor (MD)
Jeffrey Gruen, MD
Within the human genome, genetic mapping studies have identified ten regions of different chromosomes, known as DYX loci, in genetic linkage with dyslexia. The gene DCDC2, located within the DYX2 region on chromosome 6p22, has been shown to have genetic association with dyslexia in several independent studies. Functional assays of DCDC2 indicate that it may help guide the migration of neurons during early brain development. DCDC2 polymorphisms that display the strongest association with dyslexia are located in a highly GC-rich region in intron 2 known as BV677278. These polymorphisms contain several transcription factor binding sites, including the canonical 8-base recognition site for PEA3, a transcription factor known to modulate neuronal migration in mice. We hypothesized that 1) BV677278 is an enhancer element for DCDC2 that regulates its expression level, location, or timing, and that 2) PEA3 regulates DCDC2 expression by binding BV677278. To test these hypotheses we showed that PEA3 binds to regions within BV677278, and that siRNA knockdown of PEA3 appears to delay the expression of DCDC2 during neuronal differentiation of mouse cells. We concluded that PEA3 was a viable candidate transcription factor for DCDC2, with the ability to bind BV677278. Taken together, these data suggest a possible mechanism by which BV677278 polymorphisms alter PEA3 binding and DCDC2 expression, which in turn may modulate neuronal migration and affect the risk of dyslexia.
Gibson, Christopher J., "The regulation of DCDC2, a candidate gene for dyslexia" (2009). Yale Medicine Thesis Digital Library. 107.