Establishment of treatment strategy for spinal muscular atrophybased on the SMN2gene transcription control
| Project/Area Number |
22591127
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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 | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
TAKESHIMA Yasuhiro 神戸大学, 医学研究科, 教授 (40281141)
NISHIMURA Noriyuki 神戸大学, 医学研究科, 准教授 (00322719)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 小児神経学 / SMN1遺伝子 / SMN2遺伝子 / プロモーター / c.-318 GCC 挿入・欠失多型 / CREB / cAMP / 脊髄性筋萎縮症 / 転写活性 / ルシフェラーゼ / ルシフェラーゼ・アッセイ |
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| Research Abstract |
More than 95 % of spinal muscular atrophy (SMA) patients show homozygous deletion of SMN1. SMN2, a highly homologous gene of SMN1, compensates for the SMN1deletion to some degree; copy number of SMN2is inversely correlated to the clinical severity of SMA. Although the promoter sequences of the two genes are almost identical, c.-318 GCC insertion has been identified as a specific polymorphism to the SMN1 promoter. In this study, we found c.-318 GCC insertion polymorphism in the SMN2 promoter of an SMN1-deleted SMA patient with milder phenotype than expected for low copy number of SMN2. However, transcript amount of SMN2in the white blood cells was smaller than other five SMN1-deleted SMA patients, suggesting that the polymorphism did not increase the transcriptional activity. Besides, reporter gene assay using plasmid constructs with or without c.-318 GCC insertion polymorphism demonstrated that the polymorphism had a slightly negative effect on the transcription efficiency. In conclusion,c.-318 GCC insertion polymorphism in the SMN2 promoter may not be associated with the milder phenotype of the patient, suggesting the presence of non-SMN2-related modifying factors of SMA severity. Our experimental data using plasmid constructs with or without c.-318 GCC insertion polymorphism suggested that in thecase of medical treatment for SMA, it is necessary to change the kind and quantity of the SMN2 -activating medicine by the presence of c.-318 GCC insertion polymorphism.
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Report
(4 results)
Research Products
(43 results)
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[Journal Article] Spinal Muscular Atrophy: From Gene Discovery to Clinical Trials2013
Author(s)
Nurputra DK, Lai PS, Harahap NI, Morikawa S, Yamamoto T, Nishimura N, Kubo Y, Takeuchi A, Saito T, Takeshima Y, Tohyama Y, Tay SK, Low PS, Saito K, Nishio H
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Journal Title
Annals of Human Genetics
Volume: (in press)
Related Report
Peer Reviewed
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[Journal Article] Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines2012
Author(s)
Harahap IS, Saito T, San LP, Sasaki N, Gunadi, Nurputra DK, Yusoff S, Yamamoto T, Morikawa S, Nishimura N, Lee MJ, Takeshima Y, Matsuo M, Nishio H
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Journal Title
Brain Dev
Volume: 34
Issue: 3
Pages: 213-222
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] Spinal muscular atrophy patient detection and carrier screening using dried blood spots on filter paper.2012
Author(s)
Harahap NI, Harahap IS, Kaszynski RH, Nurputra DK, Hartomo TB, Pham HT, Yamamoto T, Morikawa S, Nishimura N, Rusdi I, Widiastuti R, Nishio H.
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Journal Title
Genet Test Mol Biomarkers
Volume: 16
Issue: 2
Pages: 123-129
DOI
Related Report
Peer Reviewed
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[Journal Article] Diagnosis of spinal muscular atrophy via high-resolution melting analysis symmetric polymerase chain reaction without probe: a screening evaluation for SMN1 deletions and intragenic mutations2011
Author(s)
Morikawa S, Harahap IS, Kaszynski RH, Yamamoto T, Pramudya DK, Van Pham HT, Hartomo TB, Lee MJ, Morioka I, Nishimura N, Yokoyama N, Ueno Y, Matsuo M, Nishio H.
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Journal Title
Genet Test Mol Biomarkers
Volume: 15
Issue: 10
Pages: 677-684
DOI
Related Report
Peer Reviewed
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[Journal Article] Screening of the LIX1 gene in Japanese and Malaysian patients with SMA and/or SMA-like disorder.2010
Author(s)
Sasongko TH, Gunadi, Yusoff S, Atif AB, Fatemeh H, Rani A, Marini M, Aziz CB, Zabidi-Hussin Z, Nishio H, Zilfalil BA
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Journal Title
Brain Dev.
Volume: 32
Issue: 5
Pages: 385-389
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] A polymorphic mutation, c.-32791>G, in the UGT1A1 promoter is a risk factor for neonatal jaundice in the Malay population.2010
Author(s)
Yusoff S, Takeuchi A, Ashi C, Tsukada M, Ma'amor NH, Alwi Zilfalil B, Mohd Yusoff N, Nakamura T, Hirai M, Harahap ISK, Gunadi, Lee MJ, Takaoka Y, Nishimura N, Morikawa S, Morioka I, Yokoyama N, Matsuo M, Nishio H, van Rostenberghe H.
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Journal Title
Pediatr Res.
Volume: 67
Pages: 401-406
Related Report
Peer Reviewed
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[Journal Article] Generalized epilepsy with febrile seizures plus (GEFS+)spectrum : clinical manifestations and SCN1A mutations in Indonesian patients.2010
Author(s)
Herini ES, Gunadi, Harahap IS, Yusoff S, Morikawa S, Patria SY, Nishimura N, Sunartini, Sutaryo, Takada S, Matsuo M, Nishio H
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Journal Title
EpilepsyRes.
Volume: 90
Pages: 132-139
Related Report
Peer Reviewed
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