Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Hum Mol Genet. 2019 Aug 15;28(16):2775-2784. doi: 10.1093/hmg/ddz106.
The dynein axonemal assembly factor (Dnaaf) protein family is involved in preassembly and stability of dynein arms before they are transported into the cilia. In humans, mutations in DNAAF genes lead to several diseases related to cilia defects such as primary ciliary dyskinesia (PCD; OMIM: 612518). Patients with PCD experience malfunctions in cilia motility, which can result in inflammation and infection of the respiratory tract among other defects. Previous studies have identified that a mutation in DNAAF2 results in PCD and that 40% of these patients also experience laterality defects. In an outbred genetic background, Dnaaf2 homozygotes die after birth and have left/right defects among other phenotypes. Here we characterize a novel null allele of Dnaaf2 obtained from the International Mouse Phenotyping Consortium. Our data indicate that on a defined C57bl/6NJ genetic background, homozygous Dnaaf2 mouse embryos fail to progress beyond organogenesis stages with many abnormalities including left-right patterning defects. These findings support studies indicating that hypomorphic mutations of human DNAAF2 can result in ciliary dyskinesia and identify Dnaaf2 as an essential component of cilia function in vivo.
动力蛋白轴丝组装因子（Dynein axonemal assembly factor，Dnaaf）蛋白家族参与动力蛋白臂的预组装和稳定性，然后将其运输到纤毛中。在人类中，DNAAF 基因突变导致几种与纤毛缺陷相关的疾病，如原发性纤毛运动障碍（Primary ciliary dyskinesia，PCD；OMIM：612518）。PCD 患者的纤毛运动功能出现故障，可能导致呼吸道炎症和感染等缺陷。先前的研究表明，DNAAF2 中的突变会导致 PCD，其中 40%的患者还存在侧性缺陷。在异交遗传背景下，Dnaaf2 纯合子在出生后死亡，并出现左右缺陷等表型。在这里，我们从国际小鼠表型分析联盟（International Mouse Phenotyping Consortium）获得了一种新型的 Dnaaf2 缺失等位基因。我们的数据表明，在特定的 C57BL/6NJ 遗传背景下，Dnaaf2 纯合子胚胎在器官发生阶段后无法继续发育，存在许多异常，包括左右模式缺陷。这些发现支持了人类 DNAAF2 功能减弱突变会导致纤毛运动障碍的研究，并确定 Dnaaf2 是体内纤毛功能的一个必需组成部分。
