Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.
Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.
复制标题
过早衰老综合征显示出具有CDC20突变的随机染色体数量不稳定性。
DOI：
10.1111/acel.13251
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发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Kubo A
中科院分区：
文献类型：
--
作者：
Fujita H;Sasaki T;Miyamoto T;Akutsu SN;Sato S;Mori T;Nakabayashi K;Hata K;Suzuki H;Kosaki K;Matsuura S;Matsubara Y;Amagai M;Kubo A
对基因组的损伤会加速衰老。非整倍体细胞（即染色体数目异常的细胞）的百分比在衰老过程中增加;然而，尚不清楚非整倍体增加是否会加速衰老。在这里，我们报告了一个人显示各种器官的过早衰老表型，包括早期脱发，皮肤萎缩和造血干细胞的损失;染色体数目不稳定，称为马赛克杂色非整倍体（MVA）;和纺锤体组装检查点（SAC）失败。外显子组测序鉴定了有丝分裂激活因子CDC 20中c.856C>A（p.R286S）的从头杂合种系错义突变。突变体CDC 20在有丝分裂检查点复合物（MCC）形成期间显示出较低的与BUBR 1的结合亲和力，但在MCC与后期促进复合物/环体（APC/C）-CDC 20复合物之间的相互作用期间没有显示出较低的与BUBR 1的结合亲和力。虽然CDC 20的杂合敲除不会诱导SAC失败，但突变体CDC 20的敲入诱导了培养细胞中的SAC失败和随机非整倍体，表明特定的错义突变可能是致病性的，可能是通过MCC和APC/C-CDC 20复合物之间的失衡。我们推测，加速的染色体数目不稳定性诱导人类过早衰老，这可能与干细胞的早期损失有关。这些发现可能构成身体和器官衰老的新疾病模型的基础。我们报告一个人表现出过早衰老，染色体数目不稳定，纺锤体组装检查点失败，并在CDC 20杂合错义突变。CDC 20突变体在有丝分裂检查点复合物的形成中显示出对BUBR 1的低结合亲和力，并诱导体外纺锤体组装检查点失败。该病例被假定为一种新的综合征，表明加速的染色体数目不稳定性诱导过早衰老。
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. We report an individual showing premature aging, instability of chromosome numbers, spindle assembly checkpoint failure, and a heterozygous missense mutation in CDC20. The CDC20 mutant showed low binding affinity to BUBR1 in the formation of the mitotic checkpoint complex and induced spindle assembly checkpoint failure in vitro. The case is postulated to be a novel syndrome showing that accelerated chromosome number instability induces premature aging.
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影响因子：
3.7
作者：
Hung CY;Volkmar B;Baker JD;Bauer JW;Gussoni E;Hainzl S;Klausegger A;Lorenzo J;Mihalek I;Rittinger O;Tekin M;Dallman JE;Bodamer OA
通讯作者：
Bodamer OA
影响因子：
64.8
作者：
Alfieri, Claudio;Chang, Leifu;Zhang, Ziguo;Yang, Jing;Maslen, Sarah;Skehel, Mark;Barford, David
通讯作者：
Barford, David
影响因子：
50.3
作者：
Manchado, Eusebio;Guillamot, Maria;Malumbres, Marcos
通讯作者：
Malumbres, Marcos
影响因子：
46.9
作者：
Nagai, T;Ibata, K;Miyawaki, A
通讯作者：
Miyawaki, A
影响因子：
5.8
作者：
Li, KB
通讯作者：
Li, KB