2007 Fiscal Year Final Research Report Summary
Pathological and epidemiological analysis of autism spectrum disorder based on synaptic molecules
| Project/Area Number |
18591176
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
UCHINO Shigeo National Center of Neurology and Psychiatry, National Institution of Neuroscience, Department of Neurochemistry, Section Chief (30392434)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Nobuhiko Osaka Medical Center and Research Institute for Maternal and Child Health, Department of Medical Intelligence and Planning, Director (30416242)
KUBOTA Takeo University of Yamanashi, Department of Epigenetic Medicine, Professor (70293511)
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| Project Period (FY) |
2006 – 2007
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| Keywords | autism / SHANK3 / 22q13.3 deletion syndrome / DNA diagnosis / genome / mental retardation / synapse / FISH |
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| Research Abstract |
22q13 deletion syndrome is characterized by significant language delay, mental retardation, hypotonia and autistic feature. Cumulative evidence has demonstrated that haploinsufficiency of SHANK3 gene located in 22q13.3 is the major causative factor in the neurological symptoms of this disease. Shank3, a multidomain protein containing SH3 and PDZ domains, localized in the postsynaptic density, and interacts with various synaptic molecules such as PSD-95 and glutamate receptors. The expression of Shank3 is predominantly observed during synaptogenesis. Therefore, it has been thought that Shank3 plays important roles in the formation and function of synapse in the developing brain. In this research, we analyzed the SHANK3 gene in the autistic patients showing the similar symptoms to 22q13.3 deletion syndrome without the terminal deletion of 22q13. We obtained blood samples from 127 patients after informed consent, and prepared genomic DNA from blood leucocytes. We amplified all SHANK3 exons using PCR, and analyzed the sequence by ABI 3100-avant Automated Sequencer. Then, we found several mutations within the SHANK3 gene as follows, i) deletion of 18 bp (6 amino acids) upstream of the SH3 region (1 sample), ii) point mutation caused the exchange of amino acid in the PDZ region (1 sample), iii) deletion (1 sample) or insertion (3 samples) of 10 bp-repetitious sequence downstream of exon 11. All mutations were not detected in 228 control samples. Our findings will support the recent hypothesis that major cause of autism resides in abnormalities at the synapse. To reinforce this hypothesis, we now investigate the pathological property of the mutated Shank3.
All experiments were approved by The Ethics Committee.
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