title: Brain region-specific altered expression and association of mitochondria-related genes in autism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Ayyappan
authors.initials: A
authors.lastname: Anitha
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Ismail
authors.initials: I
authors.lastname: Thanseem
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351 0198, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351 0198, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351 0198, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsuzaki
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Miyachi
authors.affiliation: Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, 183 8561, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.|Faculty of Sociology, Chukyo University, 101 Tokodachi, Toyota, 470 0393, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Tsujii
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Kenji J
authors.initials: KJ
authors.lastname: Tsuchiya
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, 183 8561, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351 0198, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Research Center for Child Mental Development, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.|Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431 3192, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Mori