Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T
Laboratoire d'Immunogénétique Humaine, INSERM E021, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris cedex 15, France.
Mol Psychiatry. 2002;7(3):302-10. doi: 10.1038/sj.mp.4000979.
A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.
此前进行了一项全基因组扫描，结果表明6号染色体q21区域是自闭症的一个候选区域。该区域包含谷氨酸受体6（GluR6或GRIK2）基因，是该综合征的一个功能候选基因。谷氨酸是大脑中的主要兴奋性神经递质，直接参与记忆和学习等认知功能。我们采用了两种不同的方法，即患病同胞对（ASP）法和传递不平衡检验（TDT），来研究GluR6与自闭症之间的连锁和关联。使用51个原始家庭和8个新的同胞对中的额外标记进行的ASP法显示，等位基因共享显著过量，产生了升高的多点最大对数似然比分数（ASPEX MLS = 3.28）。在ASP家庭和107个亲子三联体的独立数据集中进行的TDT分析表明，存在显著的母系传递不平衡（TDTall P = 0.0004）。此外，TDT分析（每个家庭仅一名患病先证者）显示GluR6与自闭症之间存在显著关联（TDT关联P = 0.008）。与母系传递相反，在不存在连锁的情况下，GluR6等位基因的父系传递符合预期，提示存在诸如印记等母系效应。对33名患病个体进行了突变筛查，发现了几个单核苷酸多态性（SNP），包括蛋白质胞质内C末端区域高度保守结构域中的一个氨基酸变化（M867I）。这种变化在8%的自闭症患者和4%的对照人群中出现，并且似乎在自闭症男性中母系传递的比例高于预期（P = 0.007）。综上所述，这些数据表明GluR6与自闭症处于连锁不平衡状态。
