Francks Clyde, Fisher Simon E, Olson Richard K, Pennington Bruce F, Smith Shelley D, DeFries John C, Monaco Anthony P
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
Psychiatr Genet. 2002 Mar;12(1):35-41. doi: 10.1097/00041444-200203000-00005.
A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.
两个独立的连锁研究表明，2号染色体p12 - 16区域的一个位点与诵读困难易感性有关，其中包括我们对119个以核型双胞胎为基础的家庭进行的研究，每个家庭至少有一个诵读困难儿童。然而，尚未有任何基因变体被报道与诵读困难相关，也没有一致的临床证据能依据任何强有力的先验逻辑来确定候选基因。我们使用了跨越2p12 - 16区域的21个微卫星标记，将我们的1-LOD单位连锁支持区间缩小至D2S337和D2S286之间的12厘摩。然后，在定量关联分析中，两个微卫星在一系列与阅读相关的测量指标上产生了P值<0.05（D2S2378和D2S2114）。对该区域内两个位置候选基因的外显子/内含子边界进行了特征分析，并对外显子进行了多态性筛查。这两个基因分别是Semaphorin4F（SEMA4F），其编码一种参与轴突生长锥导向的蛋白质；以及OTX1，其编码一种参与前脑发育的同源域转录因子。在SEMA4F中发现了两个非同义单核苷酸多态性，每个的杂合度为0.03。对SEMA4F外显子12和13之间的一个内含子单核苷酸多态性进行了定量关联测试，但未发现显著关联。在OTX1中仅发现一个单核苷酸多态性，它位于外显子但为沉默突变。因此，我们的数据表明，2p12 - 16区域与阅读障碍的连锁并非由SEMA4F或OTX1的编码变体引起。我们的研究概述了在诵读困难的流行病学人群中鉴定导致诵读困难易感性的基因变体所需的方法。
