Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and Universitair Medisch Centrum Utrecht, Uppsalalaan 8, Utrecht, The Netherlands.
Blood. 2011 Nov 17;118(20):5458-65. doi: 10.1182/blood-2011-04-351460. Epub 2011 Sep 14.
Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in nop10 mutants. Our data support a model of DC whereupon in early development mutations involved in the H/ACA complex contribute to bone marrow failure through p53 deregulation and loss of initial stem cell numbers while their role in telomere maintenance does not contribute to DC until later in life.
先天性角化不良症（DC）是一种骨髓衰竭疾病，其特征是端粒缩短、干细胞维持缺陷以及高度异质表型，主要影响需要高周转率的组织。在这里，我们介绍了一种突变的斑马鱼品系，该品系中 nop10 的表达降低，nop10 是已知与 DC 相关的 H/ACA RNP 复合物基因之一。我们证明，这种 nop10 的缺失导致 18S rRNA 加工缺陷和小核糖体亚基的崩溃，同时通过小核糖体蛋白与 Mdm2 结合稳定 p53 肿瘤抑制蛋白。这些突变体还表现出造血干细胞缺乏，而在 p53 功能丧失时可恢复。然而，我们在 nop10 突变体中没有检测到端粒长度的变化。我们的数据支持了一种 DC 模型，即在早期发育中，涉及 H/ACA 复合物的突变通过 p53 失调和初始干细胞数量的丧失导致骨髓衰竭，而它们在端粒维持中的作用在生命后期才与 DC 相关。
