| 1 | Mol Autism 2014 -1 5: 49 |
|---|---|
| PMID | 25400900 |
| Title | Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects. |
| Abstract | 组蛋白H3在9 (H3K赖氨酸甲基化9) is a conserved epigenetic signal, mediating heterochromatin formation by trimethylation, and transcriptional silencing by dimethylation. Defective GLP (Ehmt1) and G9a (EHMT2) histone lysine methyltransferases, involved in mono and dimethylation of H3K9, confer autistic phenotypes and behavioral abnormalities in animal models. Moreover, EHMT1 loss of function results in Kleefstra syndrome, characterized by severe intellectual disability, developmental delays and psychiatric disorders. We examined the possible role of histone methyltransferases in the etiology of autism spectrum disorders (ASD) and suggest that rare functional variants in these genes that regulate H3K9 methylation may be associated with ASD. Since G9a-GLP-Wiz forms a heteromeric methyltransferase complex, all the protein-coding regions and exon/intron boundaries of EHMT1,EHMT2and WIZ were sequenced in Japanese ASD subjects. The detected variants were prioritized based on novelty and functionality. The expression levels of these genes were tested in blood cells and postmortem brain samples from ASD and control subjects. Expression of EHMT1 andEHMT2isoforms were determined by digital PCR. We identified six nonsynonymous variants: three in EHMT1, two inEHMT2and one in WIZ. Two variants, the EHMT1 ankyrin repeat domain (Lys968Arg) andEHMT2SET domain (Thr961Ile) variants were present exclusively in cases, but showed no statistically significant association with ASD. TheEHMT2transcript expression was significantly elevated in the peripheral blood cells of ASD when compared with control samples; but not for EHMT1 and WIZ. Gene expression levels of EHMT1,EHMT2and WIZ in Brodmann area (BA) 9, BA21, BA40 and the dorsal raphe nucleus (DoRN) regions from postmortem brain samples showed no significant changes between ASD and control subjects. Nor did expression levels of EHMT1 andEHMT2isoforms in the prefrontal cortex differ significantly between ASD and control groups. We identified two novel rare missense variants in the EHMT1 andEHMT2genes of ASD patients. We surmise that these variants alone may not be sufficient to exert a significant effect on ASD pathogenesis. The elevated expression ofEHMT2in the peripheral blood cells may support the notion of a restrictive chromatin state in ASD, similar toschizophrenia. |
| SCZ Keywords | schizophrenia |