2007 Fiscal Year Final Research Report Summary
Molecular basis of leukodystrophy caused by a dosage-sensitive gene
| Project/Area Number |
17590287
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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 |
Human genetics
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| Research Institution | Kyushu University |
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Principal Investigator |
IWAKI Akiko Kyushu University, Medical Institute of bioregulation, Assistant Professor (30253454)
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| Project Period (FY) |
2005 – 2007
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| Keywords | gene / genome / neurological disorder |
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| Research Abstract |
The proteolipid protein gene (PLP1) on chromosome Xq22 is a dosage-sensitive gene and PLP1 duplication causes Pelizaeus-Merzbacher disease (PMD), an X-linked disorder characterized by dysmyelination in the central nervous system. To understand the nature of the genomic rearrangement, we examined the precise sequences of the duplication breakpoints of six newly identified PMD patients at nucleotide levels. The extent of duplication was systematically examined using various PAC probes along the Xq22 region by interphase FISH. We mapped approximate location of the centromeric and/or telomeric ends of the duplicated segments by quantitative multiplex PCR using sequence-tagged site primers. After detecting the rearranged restriction fragments by Southern blot hybridization, junction fragments were amplified by inverse-PCR. Sequence analysis revealed that the duplicated segments, arranged in a head to tail manner, varied from 0.3 Mb to 1 Mb in length. There was no homology between the sequences around the centromeric and the telomeric ends except for several nucleotides. Therefore, it is likely that non-homologous end joining causes PLP1 duplications in these cases. Toward the development of a therapy we generated a new vector-based expression system for an artificial miRNA precursor motif (AMPM) under the control of an RNA polymerase II promoter. The AMPM located in the intron or the exon of the selection marker gene mediated silencing of the reporter gene expression in cultured cells. Furthermore, we identified a heterozygous deletion of ITPR1 in spinocerebellar ataxia 16 and determined the deletion breakpoint. It appears that ITPR1 is a dosage-sensitive gene.
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[Journal Article] Heterozygous deletion of ITPR1, but not SUMF1 in spinocerebellar ataxia type 16.2008
Author(s)
Iwaki, A., Kawano, Y., Miura, S., Shibata, H., Matsuse, D., Li, W., Furuya, H., Ohyagi, Y., Taniwaki, T., Kira, J., Fukumaki, Y
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Journal Title
J. Med. Genet 45
Pages: 32-35
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Pelizaeus-Merzbacher disease caused by PLP1 duplication2006
Author(s)
Kenji, Kurosawa, Hitoshi, Osaka, Kaori, Masuko, Akiko, Iwaki, Hiroko, Iwamoto, Sumio, Yamashita
Organizer
The 48th Meeting of the Japanese Society of Child Neurology
Place of Presentation
Tokyo
Year and Date
2006-06-02
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Two different PLP1 abnormalities result in PLP null syndorome2005
Author(s)
Akiko, Iwaki, Naoki, Matsumoto, Akiko, Ochi, Hiroyuki, Torisu, Ryutaro, Kira, Toshiro, Hara, Kenzo, Takeshita, Yasuyuki, Fukumaki
Organizer
The 28th Annual Meeting of the Molecular Biology Society of Japan
Place of Presentation
Fukuoka
Year and Date
2005-12-08
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Pelizaeus-Merzbacher disease caused by PLP1 deletion(PLP null syndrome)2005
Author(s)
Hiroyuki, Torisu, Ryutaro, Kira, Yasunari, Sakai, Masashi, Sanefuji, Yoshimi, Takemoto, Toshiro, Hara, Kenzo, Takeshita, Akiko, Iwaki
Organizer
The 47th Meeting of the Japanese Society of Child Neurology
Place of Presentation
Kumamoto
Year and Date
2005-05-20
Description
「研究成果報告書概要(欧文)」より
