Reelin gene alleles and susceptibility to autism spectrum disorders
Reelin gene alleles and susceptibility to autism spectrum disorders
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DOI：
10.1038/sj.mp.4001124
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发表时间：
2002
影响因子：
11
通讯作者：
Huiping Zhang;X. Liu;C. Zhang;Emanuela Mundo;Emanuela Mundo;Fabio Macciardi;Fabio Macciardi;D. Grayson;Alessandro Guidotti;Jeanette J.A. Holden
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文献类型：
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作者：
Huiping Zhang;X. Liu;C. Zhang;Emanuela Mundo;Emanuela Mundo;Fabio Macciardi;Fabio Macciardi;D. Grayson;Alessandro Guidotti;Jeanette J.A. Holden
研究了人类Reelin基因（Reelin gene，CGN）中的一个多态性三核苷酸重复序列（polymorphic trinucleotide repeat，CGG/GCC）作为自闭症谱系障碍（autism spectrum disorders，ASD）的候选基因。该基因编码一个大的细胞外基质蛋白，其在皮质生成期间协调神经元定位。对126个多发性骨髓瘤家系进行了CGG重复序列检测。CGG重复的数量在受影响的个体和对照组中从3到16不等，在自闭症先证者的家庭中，在母亲（n = 291）或父亲（n = 287）的传递过程中没有观察到扩张或收缩。虽然患病儿童的等位基因和基因型频率与对照组没有差异，但基于家庭的关联检验（FBAT）显示，较大的等位基因（≥ 11次重复）传播给受影响儿童的频率高于预期（S = 43，E（S）= 34.5，P = 0.035）;尤其是对于13-重复序列的SNN等位基因（S = 22，E（S）= 16，P = 0.034）。受影响的同胞对（ASP）的分析发现，没有证据表明过度共享的等位基因在受影响的兄弟姐妹。通过ANOVA分析了具有大等位基因（≥ 11个重复）的基因型对ASD个体表型的影响，这些基因型在自闭症诊断访谈-修订版结果可用的一个家庭子集中。在与孤独症核心症状相关的问题上，携带大等位基因的儿童得分无差异，但携带至少一个大等位基因的儿童出现第一阶段的年龄有提前的趋势（χ 2 = 3.538，P = 0.06）。因此，尽管病例对照和受累同胞对的研究结果不支持ASDN在ASD易感性中的作用，但更有力的基于家族的关联研究表明，具有大量CGG重复序列的ASDN等位基因可能在某些ASD病例的病因学中发挥作用，特别是在没有延迟短语言语的儿童中。
A polymorphic trinucleotide repeat (CGG/GCC) within the human Reelin gene (RELN) was examined as a candidate gene for autism spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within the 5′ untranslated region of RELN exon 1 was examined in 126 multiple-incidence families. The number of CGG repeats varied from three to 16 in affected individuals and controls, with no expansion or contraction observed during maternal (n= 291) or paternal (n= 287) transmissions in families with autistic probands. Although the frequencies of the RELN alleles and genotypes in affected children were not different from those in the comparison group, a family-based association test (FBAT) showed that the larger RELN alleles (≥ 11 repeats) were transmitted more often than expected to affected children (S= 43, E (S)= 34.5, P= 0.035); this was particularly the case for the 13-repeat RELN allele (S= 22, E (S)= 16, P= 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing of RELN alleles in affected siblings. The impact of genotypes with large alleles (≥ 11 repeats) on the phenotypes in individuals with ASD was analyzed by ANOVA in a subset of the families for which results of the Autism Diagnostic Interview-Revised were available. Children with large RELN alleles did not show any difference in scores for questions related to the core symptoms of autistic disorder, but there was a tendency for children with at least one large RELN allele to have an earlier age at first phrase (χ 2= 3.538, P= 0.06). Thus, although the case-control and affected sib-pair findings did not support a role for RELN in susceptibility to ASD, the more powerful family-based association study demonstrated that RELN alleles with larger numbers of CGG repeats may play a role in the etiology of some cases of ASD, especially in children without delayed phrase speech.