Brain region-specific altered expression and association of mitochondria-related genes in autism.
Brain region-specific altered expression and association of mitochondria-related genes in autism.
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DOI：
10.1186/2040-2392-3-12
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发表时间：
2012-11-01
期刊：
影响因子：
6.2
通讯作者：
Mori N
中科院分区：
文献类型：
--
作者：
Anitha A;Nakamura K;Thanseem I;Yamada K;Iwayama Y;Toyota T;Matsuzaki H;Miyachi T;Yamada S;Tsujii M;Tsuchiya KJ;Matsumoto K;Iwata Y;Suzuki K;Ichikawa H;Sugiyama T;Yoshikawa T;Mori N
线粒体功能障碍（MtD）在大约5%的自闭症谱系障碍（ASD）儿童中观察到。MtD可能会损害高度依赖能量的过程，如神经发育，从而导致自闭症。以前的大多数自闭症MtD研究都局限于能量代谢的生物标志物，而大多数遗传学研究都是基于线粒体DNA（mtDNA）的突变。尽管有线粒体DNA，但大多数线粒体复制和功能所必需的蛋白质都是由基因组DNA编码的;到目前为止，对这些基因的研究很少。因此，我们进行了详细的研究，涉及基因表达和遗传关联研究的基因相关的各种线粒体功能。对于基因表达分析，从自闭症组织计划（Princeton，NJ，USA）获得来自自闭症患者（n=8）和对照（n=10）的死后脑组织（前扣带回（ACG）、运动皮层（MC）和丘脑（THL））。定量实时PCR阵列被用来量化84个基因的表达与线粒体的各种功能，包括生物发生，运输，易位和凋亡。我们使用Delta Delta Ct（Delta Delta Ct）方法来定量基因表达。来自841个高加索人和188个日本家庭的DNA样品用于从基因表达分析中选择的基因的关联研究。FBAT被用来检查与自闭症的遗传关联。与对照组相比，自闭症患者的几个基因显示出大脑区域特异性表达的改变。Metaxin 2（MTX 2）、神经丝、轻多肽（NEFL）和溶质载体家族25成员27（SLC 25 A27）在自闭症患者的ACG、MC和THL中表现出一致的表达降低。NEFL（P = 0.038; Z-评分2.066）和SLC 25 A27（P = 0.046; Z-评分1.990）分别在高加索人和日本人样本中显示出与自闭症的遗传关联。DNAJC 19、DNM 1 L、LRPPRC、SLC 25 A12、SLC 25 A14、SLC 25 A24和TOMM 20的表达在自闭症患者的至少两个脑区域中降低。我们的研究虽然是初步的，但揭示了一些与自闭症MtD相关的新基因。如果在早期阶段检测到MtD，可以采取旨在减少其影响的治疗策略。
Mitochondrial dysfunction (MtD) has been observed in approximately five percent of children with autism spectrum disorders (ASD). MtD could impair highly energy-dependent processes such as neurodevelopment, thereby contributing to autism. Most of the previous studies of MtD in autism have been restricted to the biomarkers of energy metabolism, while most of the genetic studies have been based on mutations in the mitochondrial DNA (mtDNA). Despite the mtDNA, most of the proteins essential for mitochondrial replication and function are encoded by the genomic DNA; so far, there have been very few studies of those genes. Therefore, we carried out a detailed study involving gene expression and genetic association studies of genes related to diverse mitochondrial functions. For gene expression analysis, postmortem brain tissues (anterior cingulate gyrus (ACG), motor cortex (MC) and thalamus (THL)) from autism patients (n=8) and controls (n=10) were obtained from the Autism Tissue Program (Princeton, NJ, USA). Quantitative real-time PCR arrays were used to quantify the expression of 84 genes related to diverse functions of mitochondria, including biogenesis, transport, translocation and apoptosis. We used the delta delta Ct (∆∆Ct) method for quantification of gene expression. DNA samples from 841 Caucasian and 188 Japanese families were used in the association study of genes selected from the gene expression analysis. FBAT was used to examine genetic association with autism. Several genes showed brain region-specific expression alterations in autism patients compared to controls. Metaxin 2 (MTX2), neurofilament, light polypeptide (NEFL) and solute carrier family 25, member 27 (SLC25A27) showed consistently reduced expression in the ACG, MC and THL of autism patients. NEFL (P = 0.038; Z-score 2.066) and SLC25A27 (P = 0.046; Z-score 1.990) showed genetic association with autism in Caucasian and Japanese samples, respectively. The expression of DNAJC19, DNM1L, LRPPRC, SLC25A12, SLC25A14, SLC25A24 and TOMM20 were reduced in at least two of the brain regions of autism patients. Our study, though preliminary, brings to light some new genes associated with MtD in autism. If MtD is detected in early stages, treatment strategies aimed at reducing its impact may be adopted.
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4.2
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