Project/Area Number |
18K19512
|
Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 52:General internal medicine and related fields
|
Research Institution | Nagoya University |
Principal Investigator |
Sahashi Kentaro 名古屋大学, 医学部附属病院, 病院助教 (90710103)
|
Co-Investigator(Kenkyū-buntansha) |
勝野 雅央 名古屋大学, 医学系研究科, 教授 (50402566)
|
Project Period (FY) |
2018-06-29 – 2020-03-31
|
Project Status |
Completed (Fiscal Year 2019)
|
Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
|
Keywords | 先天性ミオパチー / リードスルー / RNA編集 |
Outline of Final Research Achievements |
We identified a late-onset congenital myopathy due to a novel homozygous nonsense mutation in SEPN1. A high incidence of this autosomal recessive disorder observed in 3 cases out of 5 siblings was attributed to copy-neutral LOH in chromosome 1p36.11. Despite the loss-of-function mutation, SEPN1 was highly expressed in patients' skeletal muscle. The recoding of the mutation at the RNA level was detected in both muscle and blood cells, and the RNA editing enzyme ADAR2 was shown to catalyze this nucleotide conversion in patient fibroblasts. Furthermore, we uncovered high expression of SEPN1 mRNA and the possible recoding event in muscle of a model mouse. The finding of ADAR2-mediated attenuation of the pathology would further provide insights into alternative therapeutic approaches for genetic disorders.
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Academic Significance and Societal Importance of the Research Achievements |
我々は網羅的遺伝子解析を通じ、筋疾患家系の変異同定に成功している。骨格筋の病理所見も合わせ、重篤な先天性遺伝性疾患の高齢発症型であることが判明し、そのメカニズムの探索目的に本研究を立ち上げている。発症者生体試料に加え、作製したヒト細胞モデルおよび動物モデルを用い、編集酵素による変異相当部分の転写レベルでの正常コード化いう機構を見出しており、変異編集の遺伝子治療応用への可能性を示す重要な知見といえる。
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