DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.
DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.
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DOI：
10.1093/hmg/ddx422
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发表时间：
2018-02-01
影响因子：
3.5
通讯作者：
Johnson CA
中科院分区：
文献类型：
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作者：
Hartill VL;van de Hoek G;Patel MP;Little R;Watson CM;Berry IR;Shoemark A;Abdelmottaleb D;Parkes E;Bacchelli C;Szymanska K;Knoers NV;Scambler PJ;Ueffing M;Boldt K;Yates R;Winyard PJ;Adler B;Moya E;Hattingh L;Shenoy A;Hogg C;Sheridan E;Roepman R;Norris D;Mitchison HM;Giles RH;Johnson CA
DNAAF1 （LRRC50）是动力蛋白重链组装和纤毛运动所需的细胞质蛋白，DNAAF1突变导致原发性纤毛运动障碍（PCD; MIM 613193）。我们描述了四个家庭与DNAAF1突变和复杂的先天性心脏病（CHD）。在三个家庭中，所有受影响的个体都有典型的PCD表型。然而，另一个家庭在两个受影响的兄弟姐妹中显示出孤立的冠心病（异位），但没有PCD的临床证据。我们发现了一个纯合的DNAAF1错义突变p.l u191phe，是该家族异位的原因。在DNAAF1缺失的斑马鱼胚胎中，基因互补表明野生型人类DNAAF1可以挽救正常的心脏环，而不是p.l u191phe变体，支持这种DNAAF1错义突变的保守致病性。这一观察结果指出了冠心病和PCD之间的表型连续性，为孤立性冠心病的发病机制提供了新的见解。在进一步研究DNAAF1在动力蛋白臂组装中的功能时，我们确定了与假定的动力蛋白臂组装复合物的成员的相互作用。这些包括纤毛纤束内转运蛋白IFT88和AAA+（与各种细胞活动相关的atp酶）家族蛋白RUVBL1 （Pontin）和RUVBL2 （Reptin）。共定位研究支持这些发现，RUVBL1的缺失扰乱了DNAAF1与IFT88的共定位。我们发现RUVBL1同源基因在小鼠胚胎淋巴结和斑马鱼胚胎库普弗氏囊泡的左侧均有不对称分布，后者的不对称依赖于DNAAF1。这些结果表明，DNAAF1-RUVBL1的生物化学和遗传相互作用在对称性破坏和心脏发育中具有新的功能作用。
DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer’s vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development.
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