自闭症和线粒体 DNA 突变有关 | Plos Genetics 论文推荐

康奈尔大学纽约州伊萨卡校区的顾正龙团队日前在 Plos Genetics 上发表论文称：比起他们的家庭成员，自闭症儿童线粒体中的 DNA 上含有更多的有害突变。

来源 Medical Press

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康奈尔大学纽约州伊萨卡校区的顾正龙团队日前在 Plos Genetics 上发表论文称：比起相的家族成员，自闭症儿童线粒体中的 DNA 包含更多的有害突变。（论文信息见文末）

越来越多的研究显示[1,2]，作为细胞能量站的线粒体功能失常是自闭症的一个诱因，但是其成为诱因的生物学基础却尚不清楚。为了弄清楚线粒体功能失常与自闭症之间的遗传关联，科学家对903例自闭症儿童及其正常兄弟姐妹、母亲的线粒体DNA进行测序分析。他们发现了一种独特的异质体突变模式：在同一细胞中，突变和正常的线粒体DNA序列中同时存在。相比于正常的同辈家庭成员，自闭症儿童线粒体中潜在的有害突变要高出两倍，会改变编码蛋白的突变要高出1.5倍。随后的研究显示这些有害突变或是遗传自母亲，或是在发育过程中自发形成。

科学家们注意到，这些有害突变在较同龄人智商偏低、且不擅长社交的儿童中带来了更高的风险。在自闭症儿童的线粒体 DNA 中，这些有害突变还会增加神经系统和生长发育问题的风险。考虑到线粒体在细胞代谢中的中心作用，该发现或许能够帮助解释伴随自闭症和神经发育异常出现的代谢紊乱。综上所述，评估自闭症高风险家庭中的线粒体 DNA 突变，能够改善对这些疾病的诊断和治疗。

本文的通讯作者顾正龙博士表示：“我们的研究结果和近期有关自闭症的研究工作，希望能让人们重视对自闭症的儿童线粒体功能和DNA的深入测试，尤其是那些伴随着发育异常或相关的临床病理症状的孩子。既然多数神经发育紊乱与其伴随的儿童期发育异常疾病都表现出线粒体功能障碍，或许我们可以把线粒体缺陷作为一个共同的信号，但这还需要进一步的研究来阐明其中机制。若能从能量角度揭示神经发育紊乱的发生机制，或许能指导我们开发出以线粒体为靶点的全新疗法和预防措施”。

参考文献

1.    Rossignol DA, Frye RE.Mitochondrial dysfunction in autism spectrum disorders?: a systematic reviewand meta-analysis. MolPsychiatry.Nature Publishing Group; 2011;17: 290-314. DOI: 10.1038/mp.2010.136

2.     Goh S, Dong Z, Zhang Y,DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtypeof autism spectrum disorder: evidence from brain imaging. JAMA psychiatry. 2014;71: 665-71.DOI: 10.1001/jamapsychiatry.2014.179 

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 论文信息

【题目】Genetic Evidencefor Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism SpectrumDisorder

【作者】Yiqin Wang, MartinPicard, Zhenglong Gu

【期刊】Plos Genetics

【日期】2016.10.28

【DOI】:10.1371/journal.pgen.1006391

【摘要】Increasingclinical and biochemical evidence implicate mitochondrial dysfunction in thepathophysiology of Autism Spectrum Disorder (ASD), but little is known aboutthe biological basis for this connection. A possible cause of ASD is thegenetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet tobe thoroughly investigated in large genomic studies of ASD. Here we evaluatedmtDNA variation, including the mixture of different mtDNA molecules in the sameindividual (i.e., heteroplasmy), using whole-exome sequencing data frommother-proband-sibling trios from simplex families (n = 903) where only onechild is affected by ASD. We found that heteroplasmic mutations in autisticprobands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which weremore likely to confer deleterious effects than heteroplasmies at polymorphicmtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymousmutations (P = 0.0028) as well as a ~2.2-fold enrichment of predictedpathogenic mutations (P = 0.0016) in autistic probands compared to theirnon-autistic siblings. Both nonsynonymous and predicted pathogenic mutationsprivate to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] =1.87[1.14–3.11] and 2.55[1.26–5.51], respectively), and their influence on ASDwas most pronounced in families with probands showing diminished IQ and/orimpaired social behavior compared to their non-autistic siblings. We alsoshowed that the genetic transmission pattern of mtDNA heteroplasmies with highpathogenic potential differed between mother-autistic proband pairs andmother-sibling pairs, implicating developmental and possibly in uterocontributions. Taken together, our genetic findings substantiate pathogenicmtDNA mutations as a potential cause for ASD and synergize with recent workcalling attention to their unique metabolic phenotypes for diagnosis andtreatment of children with ASD.

【链接】http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006391

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