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DOI	10.1073/pnas.2021429118
	An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes
	Yardeni T.; Cristancho A.G.; McCoy A.J.; Schaefer P.M.; McManus M.J.; Marsh E.D.; Wallace D.C.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations. © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Autism; Mitochondrial dysfunction; ROS
语种	英语
scopus关键词	mitochondrial DNA; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); animal cell; animal genetics; animal tissue; anxiety disorder; Article; autism; brain cortex; cell count; cell function; compulsion; controlled study; disorders of mitochondrial functions; EEG abnormality; endophenotype; female; hippocampus; human; interneuron; male; missense mutation; mitochondrial respiration; mouse; ND6 gene; nonhuman; olfactory bulb; priority journal; seizure threshold; social interaction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180755
作者单位	Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Division of Child Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States
推荐引用方式 GB/T 7714	Yardeni T.,Cristancho A.G.,McCoy A.J.,et al. An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes[J],2021,118(6).
APA	Yardeni T..,Cristancho A.G..,McCoy A.J..,Schaefer P.M..,McManus M.J..,...&Wallace D.C..(2021).An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Yardeni T.,et al."An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).