A Dyslexia-Associated Variant in DCDC2 Changes Gene Expression
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Reading disability (RD) or dyslexia is a common neurogenetic disorder. Two genes, KIAA0319 and DCDC2, have been identified by association studies of the DYX2 locus on 6p21.3. We previously identified a 2445 bp deletion, and a compound STR within the deleted region (BV677278), in intron 2 of DCDC2. The deletion and several alleles of the STR are strongly associated with RD (P = 0.00002). In this study we investigated whether BV677278 is a regulatory region for DCDC2 by electrophoretic mobility shift and luciferase reporter assays. We show that oligonucleotide probes from the STR bind nuclear protein from human brain, and that alleles of the STR have a range of DCDC2-specific enhancer activities. Five alleles displayed strong enhancer activity and increased gene expression, while allele 1 showed no enhancer activity. These studies suggest that the association of BV677278 with RD reflects a role as a modifier of DCDC2 expression.
KeywordsDyslexia Reading disability DCDC2 Regulatory region Association
This study was supported by the International Dyslexia Association (R07420 to H.M.), and National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01 NS43530 to J.R.G.). The authors thank Dr. Satish Ghatpandle for kindly providing the cell lines, Dr. Patrick G. Gallagher for scientific suggestions, and Dr. Seiyu Hosono, Dr. Zhi-jia Ye, Dr. Queenie Tan, and Dr. Rong Cong for technical assistance. We also thank Susan Chan for editing the manuscript.
This manuscript describes the characterization of an enhancer element in DCDC2. Yale University has applied for a patent covering this element; authors Jeffrey Gruen and Haiying Meng are inventors on this patent. Furthermore, the patent rights have been licensed to a start-up company founded by Dr. Gruen.
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