A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure.
A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure.
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DOI：
10.1371/journal.pone.0189324
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Bodamer OA
中科院分区：
文献类型：
--
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
原始生长失败与细胞分裂和复制的生物学缺陷有关。微管纺锤体的形成、组织和功能的复杂过程已经成为这些疾病的主要病理机制。大多数已报道的疾病基因编码中心体和中心粒蛋白，留下纺锤体与染色体相互作用的动粒蛋白在很大程度上未被考虑。我们报告了一种新的疾病基因编码的组成性内着丝粒成员CENPT，这是参与着丝粒靶向和组装，导致严重的生长障碍，在两个兄弟姐妹的近亲家庭。我们在此提出的分子和细胞机制的研究，解释如何在这个基因中的基因突变导致原始生长失败。在这两个，受影响的人类细胞系和斑马鱼敲除模型的Cenpt，我们观察到细胞分裂异常与微核和细胞核的异常积累与DNA含量增加所产生的不完全和/或不规则的染色体分离。我们的研究强调了动粒功能对整体身体生长的至关重要性，并为这些严重生长障碍的细胞机制提供了新的见解。
Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders.
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影响因子：
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作者：
Gilmore, Edward C.;Walsh, Christopher A.
通讯作者：
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影响因子：
6.8
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Harris WA
影响因子：
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作者：
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