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Brain region-specific altered expression and association of mitochondria-related genes in autism

Ayyappan Anitha1, Kazuhiko Nakamura2*, Ismail Thanseem2, Kazuo Yamada3, Yoshimi Iwayama3, Tomoko Toyota3, Hideo Matsuzaki1, Taishi Miyachi1, Satoru Yamada4, Masatsugu Tsujii15, Kenji J Tsuchiya1, Kaori Matsumoto1, Yasuhide Iwata2, Katsuaki Suzuki1, Hironobu Ichikawa4, Toshiro Sugiyama6, Takeo Yoshikawa3 and Norio Mori12

Author Affiliations

1 Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan

2 Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan

3 Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351 0198, Japan

4 Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu, 183 8561, Japan

5 Faculty of Sociology, Chukyo University, 101 Tokodachi, Toyota, 470 0393, Japan

6 Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan

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Molecular Autism 2012, 3:12  doi:10.1186/2040-2392-3-12

Published: 1 November 2012



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.

Autism; Mitochondria; Postmortem brain; NEFL; Uncoupling protein; Metaxin