Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms
Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms
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DOI：
10.1016/j.ajhg.2018.03.025
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发表时间：
2018-05-03
影响因子：
9.8
通讯作者：
Omran, Heymut
中科院分区：
文献类型：
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作者：
Hoeben, Inga M.;Hjeij, Rim;Omran, Heymut
原发性纤毛运动障碍（PCD）的特征是慢性气道疾病，男性不育，由于纤毛和精子鞭毛的运动缺陷而导致左/右身体轴的随机化。我们在来自五个不同家族的PCD个体中发现了开放阅读框C11orf70的功能缺失突变。透射电镜分析和高分辨率免疫荧光显微镜显示，C11orf70的功能缺失突变分别导致呼吸纤毛和精子鞭毛的不动，这是由于轴突外臂（ODAs）和内动力蛋白臂（IDAs）的缺失，表明C11orf70参与了动力蛋白臂的细胞质组装。C11orf70的表达分析表明，C11orf70在纤毛呼吸细胞中表达，并且C11orf70的表达在纤毛发生过程中上调，类似于其他先前描述的细胞质动力臂组装因子。此外，C11orf70显示出与细胞质ODA/IDA组装因子DNAAF2的相互作用，支持了我们关于C11orf70是参与PCD发病机制的预组装因子的假设。识别导致PCD和男性不育的其他遗传缺陷对临床和遗传咨询都非常重要。
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.