Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation

Harumi Fujita, Takashi Sasaki, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Showbu Sato, Takehiko Mori, Kazuhiko Nakabayashi, Kenichiro Hata, Hisato Suzuki, Kenjiro Kosaki, Shinya Matsuura, Yoichi Matsubara, Masayuki Amagai, Akiharu Kubo

研究成果: Article査読

9 被引用数 (Scopus)


Damage to the genome can accelerate aging. The percentage of aneuploid cells, that is, cells with an abnormal number of chromosomes, increases during aging; however, it is not clear whether increased aneuploidy accelerates aging. Here, we report an individual 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 spindle assembly checkpoint (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 BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex/cyclosome (APC/C)–CDC20 complex. While heterozygous knockout of CDC20 did not induce SAC failure, knock-in of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the particular missense mutation is pathogenic probably via the resultant imbalance between MCC and APC/C-CDC20 complex. We postulate that accelerated chromosome number instability induces premature aging in humans, which may be associated with early loss of stem cells. These findings could form the basis of a novel disease model of the aging of the body and organs.

ジャーナルAging Cell
出版ステータスPublished - 2020 11月

ASJC Scopus subject areas

  • 加齢科学
  • 細胞生物学


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