Department of Paediatrics and Adolescent Medicine, University Hospital 79106 Freiburg, Germany.
Am J Hum Genet. 2009 Dec;85(6):883-9. doi: 10.1016/j.ajhg.2009.10.018.
Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Here, we demonstrate that large genomic deletions, as well as point mutations involving LRRC50, are responsible for a distinct PCD variant that is characterized by a combined defect involving assembly of the ODAs and IDAs. Functional analyses showed that LRRC50 deficiency disrupts assembly of distally and proximally DNAH5- and DNAI2-containing ODA complexes, as well as DNALI1-containing IDA complexes, resulting in immotile cilia. On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes.
影响纤毛和鞭毛运动的遗传缺陷导致慢性破坏性气道疾病、左右身体不对称的随机化，以及原发性纤毛运动障碍（PCD）中经常发生的男性不育。最常见的缺陷涉及外动力臂和内动力臂（ODAs 和 IDAs），它们是负责纤毛摆动产生和调节的大型多蛋白复合物。在这里，我们证明了大片段基因缺失以及涉及 LRRC50 的点突变是导致一种独特的 PCD 变体的原因，该变体的特征是涉及 ODAs 和 IDAs 的组装缺陷。功能分析表明，LRRC50 缺乏会破坏 DNAH5 和 DNAI2 包含的 ODAs 复合物以及包含 DNALI1 的 IDAs 复合物的远端和近端组装，导致无运动纤毛。基于这些发现，我们假设 LRRC50 在不同的动力臂复合物的组装中发挥作用。
