Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
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DOI：
10.1038/ng.1106
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发表时间：
2012-03-04
期刊：
影响因子：
30.8
通讯作者：
Mitchell, David R.
中科院分区：
文献类型：
--
作者：
Mitchison, Hannah M.;Schmidts, Miriam;Loges, Niki T.;Freshour, Judy;Dritsoula, Athina;Hirst, Rob A.;O'Callaghan, Christopher;Blau, Hannah;Al Dabbagh, Maha;Olbrich, Heike;Beales, Philip L.;Yagi, Toshiki;Mussaffi, Huda;Chung, Eddie M. K.;Omran, Heymut;Mitchell, David R.
原发性纤毛运动障碍 (PCD) 最常见的原因是驱动纤毛跳动的动力蛋白马达丧失。在这里，我们表明，PF22/DNAAF3（一种以前未表征的蛋白质）对于动力蛋白在运输到纤毛之前预组装成复合物至关重要。我们在患有内逆位和内外动力蛋白臂组装缺陷家族的患者中发现了人类 DNAAF3 基因的功能丧失突变。斑马鱼 dnaaf3 敲低同样会破坏动力蛋白臂组装和纤毛运动，导致 PCD 表型，包括脑积水和偏侧畸形。莱茵衣藻 PF22 完全是细胞质的，无效突变体无法组装外部和一些内部动力蛋白臂。突变细胞质中动力蛋白亚基丰度的改变表明 PF22/DNAAF3 在动力蛋白预装配途径中与其他预装配蛋白 PF13/KTU 和 ODA7/LRRC50 处于相似的阶段。这些结果支持了具有组装能力的睫状动力蛋白复合物的细胞质形成的保守多步骤途径的存在。
Primary Ciliary Dyskinesia (PCD) most often arises from loss of the dynein motors that power ciliary beating. Here we show that PF22/DNAAF3, a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes prior to their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in patients from families with situs inversus and defects in assembly of inner and outer dynein arms. Zebrafish dnaaf3 knockdown likewise disrupts dynein arm assembly and ciliary motility, causing PCD phenotypes including hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a null mutant fails to assemble outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests PF22/DNAAF3 acts at a similar stage to other preassembly proteins, PF13/KTU and ODA7/LRRC50, in the dynein preassembly pathway. These results support the existence of a conserved multi-step pathway for cytoplasmic formation of assembly-competent ciliary dynein complexes.
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影响因子：
5.3
作者：
Geremek, Maciej;Bruinenberg, Marcel;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca
影响因子：
3.8
作者：
Coren, ME;Meeks, M;Bush, A
通讯作者：
Bush, A
影响因子：
4.8
作者：
Freshour, Judy;Yokoyama, Ruth;Mitchell, David R.
通讯作者：
Mitchell, David R.
影响因子：
9.8
作者：
Castleman, Victoria H.;Romio, Leila;Mitchison, Hannah M.
通讯作者：
Mitchison, Hannah M.
影响因子：
2.9
作者：
Hom, Erik F. Y.;Witman, George B.;Harris, Elizabeth H.;Dutcher, Susan K.;Kamiya, Ritsu;Mitchell, David R.;Pazour, Gregory J.;Porter, Mary E.;Sale, Winfield S.;Wirschell, Maureen;Yagi, Toshiki;King, Stephen M.
通讯作者：
King, Stephen M.