讀寫障礙是最普遍的一種學習障礙（80%)，影響全球大約一成的學童。讀寫障礙患者於閱讀及書寫能力方面出現困難，而這並非因為患者本身的智力、學習動機或學習機會引致。對於引至讀寫障礙的理仍未清楚，但在西方人士的遺傳研究方面已發現多個與讀寫障礙相聯的基因位點及基因。本研究針對其中4個基因位點（DYX1 ’ DYX2 ’ DYX3 ’ DKX8)及其覆蓋的11基因測試了 131讀寫障礙的中國人家庭與讀寫障礙的關聯性。是項研究從國際人類基因組單體型圖(HapMap)中選擇標籤單核苷酸多型性(Tag-SNPs)及選擇以往報告與讀寫障礙有關的單核苷酸多型性進行測試。並在DYXZa基因（rs3743205 ’ padjusted =0.0072' OR = 0.08 ( 95% CI: 0.01 - 0.64 ))私MRPL19 (風險單体型rs2422229-rs7570229,風險單体型T-G, Padjusted=0.0020, OR = 2.345 (95% CI: 1.402 - 3.923))發現與讀寫障礙有正關聯性。單核苷酸多態性亦與閱讀的幾個特徵相關：DYX1C1 ( rs3743205 )與快速命名（Digit Rapid Naming ) ’語音記憶（Non-word repetition)，字型結構的左右逆轉（Left-Right Reversal )相關；KIAA0319 ( rs2760157 rs807507 )與語音意識（Onset Detection )相關；MRPL19 ( rs2422229-rs7570229 ) 與字型結構的部首位置(Radical Position)相關；SFPQand ZMYM4 ( rs3738697 - rs12093076 )與詞彙決策（Lexical Decision )相關。本研究是首個對於讀寫障礙的中國人族群進行的的基因研究（Lim et al. 2011) ’結果有助提供我們了解讀寫障礙在使用不同語言的族群的情況。 / 在過往歐洲的研究樣本中’位於KAA0319基因5'-上游的基因變異重複地被找出與讀寫障礙有關的閱讀特徵有關。過往研究亦指出位於KIAA0319的假定調控區上的單核苷酸多態性(SNP)顯示與KIAA0315的基因表達有關。唯本項研究於這區域並無發現陽性結果。為了找出這區域中與讀寫障礙有關聯但未被本研究策略選擇使用基因組單體型圖的標籤-單核苷酸多態性(Hapmap Tag-SNPs)的基因變異，本研究對KAM0319基因的5'-上游進行了基因组重测序。其中發現的3個短序變異（-121的rs6456625，-128到- 1 5 4 的r s 7 1 8 1 5 1 4 3 及- 1 5 7 的6 > A )出現了不同的榮光素酶報告基因活動，當中單体型A-DEL-A的活動訊號最高，而G-INS-G則最低。然而，它們的等位基因和單体型基因出現率於讀寫障礙樣本與對照組沒有顯著不同。 / 至今有關對KIAA0319基因抑制的行為研究仍然不足。本研究亦對位於果繩的CG7565基因，即KIAA0319的同源基因’進行特性分析。CG7565在果繩的發展階段出現了不同的表達水平及基因剪接形式。本研究使用了UAS-RNAi糸統和飛行模擬器對CG7565基因抑制的果繩的行為變化作出了分析，結果顯示於泛神經基因抑制晰/+; e/aV-Gal4/+; 3707/+及晰/+; e/av-Gal4/+; 8396/+的果蠅視覺模式記憶出現了缺陷。當CG7565在果繩大腦中央複合區的神經元F5(扇形體)和R2/R4m(摘球体)被基因抑制時，果繩視覺模式記憶亦出現了缺陷。是次有關M/PL119的遺傳關聯研究跟以往MRPL19中5'-上游與讀寫障礙的關聯報導的一致’顯示這可能是真正的致病序列變異的位置。在M/PL119上的假定調控區進行基因突變分析顯示，在其中一個讀寫障礙的樣本中發現一個新的序列變化(-647 T>G)，而在對照組則沒有發現此變化。計算機預測模型分析估計這個序列變化會取消了熱休克轉錄因子1的結合位點。攜帶了 G等位基因的調控區會增加榮光素酶的活動。這種變異的作用必須得到進一步的證實。我們亦觀察到在其中兩個讀寫障礙樣本中出現了非孟德爾遺傳，在一個個体身上帶有3或4種單倍型的基因。基因拷貝數目變異或基因轉換可能是一個引至這種現象的因素。 / Developmental dyslexia is a learning disability characterized by difficulties in acquisition of reading and writing skills not due to intelligence, motivation or schooling. Being the most common form of learning disability (80%), it affects 10% of schoolchildren worldwide. Research delineating genetic factors in developmental dyslexia identified loci and candidate genes in Caucasian populations, although disease mechanisms are still unknown. Four loci covering eleven genes (DYX1, DYX2, DYX3, DYXS) were tested for association in 131 Chinese families with dyslexic children in our study. Tagged-SNPs selected from International HapMap Consortium and reported SNPs were used as markers for this study. Positive associations with dyslexia were found in two genes, DYX1C1 (rs3743205, padjusted=0.0072, OR =0.08 (95% CI: 0.01 - 0.64)) and MRPL19(rs2422229-rs7570229, risk haplotype T-G,Padjusted=0.0020, OR = 2.345 (95% CI: 1.402 一 3.923)), in our study. SNPs associated with several reading-related traits were also identified: DYX1C1(rs3743205) associated with Rapid Naming (Digit Rapid Naming), Phonological Memory (Non-word repetition),Orthographic skill (Left-Right Reversal); KIAA0319 (rs2760157-rs807507) with honological awareness (Onset Detection); MRPL19 (rs2422229-rs7570229) with Orthographic knowledge (Radical Position); SFPQ and ZMYM4 (rs3738697 - rs12093076) with Orthographic knowledge (Lexical Decision). This is the first genetic study in Chinese dyslexia (Lim et al.2011), and results provide knowledge into dyslexia in populations using different languages. / Variants located 5' upstream of KIAA0319 were consistently reported for association with DD reading-related traits in European samples. A SNP in the putative promoter of KIAA0319 showed functional significance in KIAA0319 expression. However, no positive result of this region is found in this study. Resequencing of the 5' upstream of KIAA0319 was done to reveal potentially associated variants not selected using current strategies in genetic association (Hapmap Tagged-SNPs). A short sequence fragment of 3 variants (-121 rs6456625, -128 to -154 rs71815143 and -157 G>A) show differential luciferase activities, haplotype A-del-A have highest signal, G-Ins-G the lowest. However, allele and haplotype frequencies in dyslexia samples were not significantly different from controls. / Direct behavioral study of KIAA0319-knockdown is still inadequate. A homolog of KIAA0319, CG7565 in Drosophila, was characterized. Differential gene expression and splicing forms were observed during Drosophila development stages. Using UAS-RNAi system and flight simulator to study behavioral change in CG7565-knockdown Drosophila showed pan-neural knockdown lines w/+; elav-Gal4/+; 3707/+ and w/+; elav-Gal4/+; 8396/+ are defective in visual pattern memory. The study of neuronal specific knockdown showed this memory was impaired when CG7565 was selectively knocked down in F5 neuron (fan-shaped body) and R2/R4m (ellipsoid body) of the central complex in Drosophila brain. / Our genetic association study of MRPL19 agrees with reports of the association of 5' upstream of MRPL19 with DD, showing that true causative sequence variants may lie here. Mutational analyses of the putative promoter of MRPL19 revealed a novel sequence change T>G at -647 in a dyslexic sample not found in controls. In-silico analysis indicates a binding site of heat shock factor-1 that is predicted to be abolished by this variant. Luciferase activity increased in the promoter carrying the G allele. The role of this variant must be confirmed. Non-Mendelian Inheritance was observed in 2 individual dyslexic samples with 3 and 4 types of haplotypes. Copy number variation or gene conversion may be a factor. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Lim, King Poo. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 201-225). / Abstracts also in Chinese. / Dedication --- p.I / Abstract --- p.II / 摘要 --- p.IV / Acknowledgements --- p.V / Table of contents --- p.VI / List of Figures --- p..XI / List of Tables --- p.XIV / List of Abbreviations --- p.XVII / Chapter 1. --- Chapter 1 --- p.1 / Genetic Association of dyslexia-candidate genes in Chinese children with dyslexia --- p.1 / Chapter 1.1. --- Introduction --- p.2 / Chapter 1.2. --- Prevalence --- p.4 / Chapter 1.3. --- Definition --- p.7 / Chapter 1.4. --- Theories of developmental dyslexia --- p.9 / Chapter 1.4.1. --- Phonological deficit theory --- p.9 / Chapter 1.4.2. --- Double deficit hypothesis --- p.10 / Chapter 1.4.3. --- Cerebellar deficit theory --- p.11 / Chapter 1.4.4. --- Magnocellular deficit theory --- p.12 / Chapter 1.4.5. --- Deficits in Chinese people with dyslexia --- p.12 / Chapter 1.5. --- Neurobiological aspects of Dyslexia --- p.15 / Chapter 1.5.1. --- Postmortem studies --- p.15 / Chapter 1.5.2. --- Structural Neuroimaging studies of dyslexia --- p.16 / Chapter 1.5.3. --- Functional Neuroimaging studies --- p.17 / Chapter 1.5.4. --- fMRI results in Chinese --- p.18 / Chapter 1.6. --- Genetics of Dyslexia --- p.19 / Chapter 1.6.1. --- Familial studies --- p.19 / Chapter 1.6.2. --- Twin studies --- p.21 / Chapter 1.6.3. --- Mode of Inheritance --- p.24 / Chapter 1.6.4. --- Genetic mapping of disease gene --- p.26 / Linkage analysis --- p.26 / Association study --- p.29 / Molecular genetic findings in dyslexia --- p.33 / Chapter 1.6.5. --- Statement of Research Rationale --- p.47 / Chapter 1.6.6. --- Objectives --- p.48 / Chapter 1. --- Chapter 2 --- p.49 / Genetic association of dyslexia-candidate genes in Chinese children with dyslexia --- p.49 / Chapter 2.1. --- Introduction --- p.50 / Chapter 2.2. --- Materials and methods --- p.51 / Chapter 2.2.1. --- Subjects --- p.51 / Chapter 2.2.2. --- DNA extraction and genotyping --- p.54 / Chapter 2.2.3. --- SNP marker selection --- p.55 / Chapter 2.2.4. --- Statistical analyses --- p.57 / Chapter 2.3. --- Results --- p.59 / Chapter 2.3.1. --- DYX1C1 --- p.59 / Single marker analysis --- p.59 / Haplotype analyses --- p.62 / Chapter 2.3.2. --- KIAA0319 --- p.67 / Association of KIAA0319 with Chinese dyslexic children --- p.67 / Association of KIAA0319 with reading related traits --- p.67 / Chapter 2.3.3. --- DCDC2 --- p.74 / Association of DCDC2 with Chinese dyslexic children --- p.74 / Chapter 2.3.4. --- MRPL19 and C2orf3 --- p.78 / Haplotypes located within 5' upstream of MRPL19 are significantly associated with DD --- p.78 / Association of the 5' upstream variants with reading related traits --- p.79 / Chapter 2.3.5. --- KIAA0319L and its surrounding genes --- p.85 / Association of KIAA03190L and its surrounding genes with Chinese dyslexic children --- p.85 / Chapter 2.3.6. --- Gene-Gene interaction analyses --- p.88 / Chapter 2.3.7. --- Parent-of-origin analysis --- p.92 / Chapter 2.4. --- Discussion --- p.94 / Chapter 2.4.1. --- DYX1C1 variant associated with DD and reading skills --- p.94 / Chapter 2.4.2. --- KIAA0319 associated with phonological awareness in Chinese --- p.99 / Chapter 2.4.3. --- DCDC2 is not associated with DD in Chinese children --- p.108 / Chapter 2.4.4. --- Association of MRPL19 and C2ORF3 in a Chinese sample --- p.111 / Chapter 2.4.5. --- Association of KIAA03190L and its surrounding genes with Chinese children with dyslexia --- p.115 / Chapter 2.4.6. --- Gene-Gene interaction --- p.118 / Chapter 2.4.7. --- Parent-of-origin --- p.119 / Chapter 2.5. --- Summary --- p.122 / Chapter 3. --- Chapter 3 --- p.126 / Resequencing analyses and characterization of 5' upstream of KIAA0319 --- p.126 / Chapter 3.1. --- Introduction --- p.127 / Chapter 3.2. --- Materials and Methods --- p.129 / Chapter 3.2.1. --- DNA samples --- p.129 / Chapter 3.2.2. --- DNA re-sequencing --- p.129 / Chapter 3.2.3. --- KIAA0319 Promoter constructs --- p.131 / Chapter 3.2.4. --- Luciferase Reporter Assays --- p.133 / Chapter 3.2.5. --- In-silico sequence analyses --- p.133 / Chapter 3.3. --- Results --- p.134 / Chapter 3.4. --- Discussion --- p.143 / Chapter 4. --- Chapter 4 --- p.148 / Characterization of CG7565, a homolog of KIAA0319, in a Drosophila model --- p.148 / Chapter 4.1. --- Introduction --- p.149 / Chapter 4.2. --- Methods and Materials --- p.152 / Chapter 4.2.1. --- Drosophila stock --- p.152 / Chapter 4.2.2. --- Sequence analyses --- p.153 / Chapter 4.2.3. --- RNA extraction and quantitative reverse-transcription PCR (RT-PCR) --- p.153 / Chapter 4.2.4. --- Behavioral Assays --- p.156 / Visual pattern memory assays --- p.156 / Optomotor Response Assays --- p.158 / Visual Discrimination Analyses --- p.159 / Chapter 4.3. --- Results --- p.160 / Chapter 4.4. --- Discussion --- p.174 / Chapter 5. --- Chapter 5 --- p.181 / Mutational analyses of 5' region of MRPL19 in children with dyslexia --- p.181 / Chapter 5.1. --- Introduction --- p.182 / Chapter 5.2. --- Materials and Methods --- p.183 / Chapter 5.2.1. --- DNA samples --- p.183 / Chapter 5.2.2. --- High resolution melting analyses (HRM) --- p.183 / Chapter 5.2.3. --- MRPL19 promoter constructs --- p.185 / Chapter 5.2.4. --- In-silico sequence analyses --- p.186
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_328387 |
| Date | January 2012 |
| Contributors | Lim, King Poo., Chinese University of Hong Kong Graduate School. Division of Biomedical Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography |
| Format | electronic resource, electronic resource, remote, 1 online resource (xviii, 226 leaves) : ill. (some col.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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