Characterization of a patient with premature aging phenotype showing random chromosome number instabilities
| Project/Area Number |
18K16040
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Keio University |
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Principal Investigator |
FUJITA Harumi 慶應義塾大学, 医学部(信濃町), 特任助教 (30736971)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 染色体分配 / 老化 / 紡錘体チェックポイント / 染色体 |
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| Outline of Final Research Achievements |
The spindle assembly checkpoint (SAC) ensures proper chromosome segregation during mitosis. Here, we identified a patient showing premature aging phenotypes of various organs including early hair loss, atrophic skin, and loss of hematopoietic stem cells; instability of chromosome numbers known as mosaic variegated aneuploidy (MVA); and SAC failure. Exome sequencing identified a de novo heterozygous germline missense mutation of c.856C>A (p.R286S) in the mitotic activator CDC20. The mutant CDC20 showed lower binding affinity to KEN-box in N-terminus of BUBR1, an important regulator of SAC. Knock-in of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that this particular missense mutation is pathogenic. Our findings indicate that CDC20 is a novel causative gene of MVA syndrome and suggest that SAC defects could cause premature aging in humans, which may be associated with early loss of stem cells.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、我々の知る限り、染色体分配異常と早老性を呈するヒト患者をはじめて見出し、解析を行った研究である。本研究により下記の学術的に新規な発見が得られた。
・CDC20がヒトにおいて染色体数不安定性を招く新規原因遺伝子であることが明らかになった。
・本研究により、ヒトにおいて染色体分配異常と早老性に相関がある可能性がはじめて示唆された。特に、既知の早老症の多くはゲノムDNA損傷の蓄積により発症すると考えられているが、ヒトにおいて染色体分配異常が老化症状をまねく可能性があることがはじめて示唆された。
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Report
(4 results)
Research Products
(2 results)
