PDF(Pubmed)
Abstract：
WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
摘要：
WDR44通过调节RAB11依赖性囊泡运输来防止纤毛发生。这里,我们描述了在X连锁基因产物WDR44的WD40重复序列（WDR）内具有错义和无义变异的男性患者，显示我们可以在斑马鱼中建模的纤毛相关发育表型。患者表型谱包括发育迟缓/智力障碍，低张力,独特的颅面特征和大脑的可变存在，肾,心脏和肌肉骨骼异常。我们证明了与更严重的疾病相关的WDR44变体会损害纤毛发生的起始和纤毛信号。因为WDR44负调节纤毛发生，令人惊讶的是，致病性错义变体显示出减少的丰度，我们将其与WDR自主重复的错误折叠和蛋白酶体的降解联系起来。我们发现疾病的严重程度与RAB11结合增加相关，我们建议驱动纤毛发生启动失调。最后,我们发现WDR和含有RAB11结合域(RBD)的NH2末端区域之间的域间相互作用,并显示患者变异破坏了这种关联.这项研究为WDR44WDR结构提供了新的见解，并描述了可能由纤毛发生受损引起的新综合征。
