RESUMO
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.
Assuntos
Alelos , Dislexia/genética , Expressão Gênica/genética , Variação Genética/genética , Proteínas Associadas aos Microtúbulos/genética , Encéfalo/metabolismo , Linhagem Celular , Deleção Cromossômica , Ensaio de Desvio de Mobilidade Eletroforética , Elementos Facilitadores Genéticos , Ligação Genética , Humanos , Íntrons/genética , Repetições de Microssatélites/genética , Sondas de Oligonucleotídeos , Sequências Reguladoras de Ácido Nucleico/genéticaRESUMO
OBJECTIVE: The purpose of this investigation was to determine whether there is an association between the putative reading disability (RD) susceptibility gene Doublecortin Domain Containing 2 (DCDC2), and gray matter (GM) distribution in the brain, in a sample of healthy control individuals. METHOD: Fifty-six control subjects were genotyped for an RD-associated deletion in intron 2 of DCDC2. Voxel based morphometry (VBM) was used to examine structural magnetic resonance imaging (MRI) scans to assess GM differences between the two groups. RESULTS: Individuals heterozygous for the deletion exhibited significantly higher GM volumes in reading/language and symbol-decoding related brain regions including superior, medial and inferior temporal, fusiform, hippocampal/para-hippocampal, inferior occipito-parietal, inferior and middle frontal gyri, especially in the left hemisphere. GM values correlated with published data on regional DCDC2 expression in a lateralized manner. CONCLUSIONS: These data suggest a role for DCDC2 in GM distribution in language-related brain regions in healthy individuals.