Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2324, USA.
Dev Cell. 2010 Mar 16;18(3):410-24. doi: 10.1016/j.devcel.2009.12.022.
Centrosomes and their component centrioles represent the principal microtubule organizing centers of animal cells. Here, we show that the gene underlying orofaciodigital syndrome 1, Ofd1, is a component of the distal centriole that controls centriole length. In the absence of Ofd1, distal regions of centrioles, but not procentrioles, elongate abnormally. These long centrioles are structurally similar to normal centrioles but contain destabilized microtubules with abnormal posttranslational modifications. Ofd1 is also important for centriole distal appendage formation and centriolar recruitment of the intraflagellar transport protein Ift88. To model OFD1 syndrome in embryonic stem cells, we replaced the Ofd1 gene with missense alleles from human OFD1 patients. Distinct disease-associated mutations cause different degrees of excessive or decreased centriole elongation, all of which are associated with diminished ciliogenesis. Our results indicate that Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.
中心体及其组成的中心粒是动物细胞的主要微管组织中心。在这里，我们发现口面指（趾）综合征 1（OFD1）的致病基因是控制中心粒长度的远端中心粒的组成部分。在没有 Ofd1 的情况下，中心粒的远端区域，而不是前中心粒，会异常伸长。这些长中心粒在结构上与正常中心粒相似，但含有不稳定的微管和异常的翻译后修饰。Ofd1 对于中心粒远端附属物的形成和鞭毛内运输蛋白 Ift88 的中心粒募集也很重要。为了在胚胎干细胞中模拟 OFD1 综合征，我们用人 OFD1 患者的错义等位基因替换了 Ofd1 基因。不同的疾病相关突变导致不同程度的中心粒过度或减少伸长，所有这些都与纤毛生成减少有关。我们的结果表明，Ofd1 在远端中心粒上发挥作用，构建远端附属物，募集 Ift88，并稳定中心粒微管的特定长度。
