Loss-of-Function Mutations in LRRC6, a Gene Essential for Proper Axonemal Assembly of Inner and Outer Dynein Arms, Cause Primary Ciliary Dyskinesia
Loss-of-Function Mutations in LRRC6, a Gene Essential for Proper Axonemal Assembly of Inner and Outer Dynein Arms, Cause Primary Ciliary Dyskinesia
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DOI：
10.1016/j.ajhg.2012.10.003
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发表时间：
2012-11-02
影响因子：
9.8
通讯作者：
Amselem, Serge
中科院分区：
文献类型：
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作者：
Kott, Esther;Duquesnoy, Philippe;Amselem, Serge
原发性纤毛运动障碍（PCD）是一组由纤毛和精子鞭毛缺陷引起的常染色体隐性遗传疾病，可导致呼吸道感染和男性不育。大多数相关基因编码参与轴丝成分组成的结构蛋白，如动力蛋白臂（DA），对纤毛和鞭毛运动至关重要;它们解释了不到一半受影响个体的病理。我们进行这项研究，以进一步了解PCD的发病机制，由于缺乏这两个DA。我们通过纯合性作图确定了LRRC 6的早期移码，LRRC 6是一种编码富含亮氨酸重复序列（LRR）的蛋白质的基因。随后对该基因的分析主要在睾丸和呼吸细胞中表达，在几个独立的个体中发现了双等位基因突变。在其中两个中观察到的位置倒置支持LRRC 6在胚胎结纤毛中的关键作用。对气道上皮细胞中天然LRRC 6的研究表明，它定位于细胞质和纤毛内，而具有功能丧失突变的细胞中不存在LRRC 6，其中DA蛋白标记物也缺失。这些结果与透射电子显微镜数据一致，显示LRRC 6突变个体的纤毛或鞭毛中不存在两种DA。尽管LRRC 6和DNAAF 1（另一种参与相同PCD表型的含LRR的蛋白质）之间存在结构和功能相似性，但这两种蛋白质并不是冗余的。因此，进化上保守的LRRC 6作为DA组装的额外参与者出现，这是一个对正确的轴丝构建至关重要的过程，并且似乎比以前认为的要复杂得多。
Primary ciliary dyskinesia (PCD) is a group of autosomal-recessive disorders resulting from cilia and sperm-flagella defects, which lead to respiratory infections and male infertility. Most implicated genes encode structural proteins that participate in the composition of axonemal components, such as dynein arms (DAs), that are essential for ciliary and flagellar movements; they explain the pathology in fewer than half of the affected individuals. We undertook this study to further understand the pathogenesis of PCD due to the absence of both DAs. We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein. Subsequent analyses of this gene mainly expressed in testis and respiratory cells identified biallelic mutations in several independent individuals. The situs inversus observed in two of them supports a key role for LRRC6 in embryonic nodal cilia. Study of native LRRC6 in airway epithelial cells revealed that it localizes to the cytoplasm and within cilia, whereas it is absent from cells with loss-of-function mutations, in which DA protein markers are also missing. These results are consistent with the transmission-electron-microscopy data showing the absence of both DAs in cilia or flagella from individuals with LRRC6 mutations. In spite of structural and functional similarities between LRRC6 and DNAAF1, another LRR-containing protein involved in the same PCD phenotype, the two proteins are not redundant. The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly, a process that is essential for proper axoneme building and that appears to be much more complex than was previously thought.