Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss‐of‐function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy‐related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense‐mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF‐variants cause a ciliopathy with features of Joubert syndrome.

中文翻译：

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CBY1 缺失会导致以 Joubert 综合征为特征的纤毛病


纤毛病是临床和遗传异质性疾病。我们研究了来自两个独立家庭的三名患者，这些患者表现出朱伯特综合征的特征：婴儿期呼吸模式异常、发育迟缓/智力障碍、小脑性共济失调、磁共振成像扫描上的磨牙征和多指畸形。我们在CBY1中发现了双等位基因功能丧失（LOF）变异，与家族中 Joubert 综合征的临床特征分离。 CBY1 定位于母体中心粒的远端，有助于纤毛的形成和功能。根据受影响个体的临床和突变发现，我们证明斑马鱼中 Cby1 的缺失会导致纤毛病相关表型。与对照组相比，患者的 CBY1 转录物水平降低，表明突变转录物通过无义介导的信使 RNA 衰减而降解。因此，我们可以通过免疫荧光检测到对照成纤维细胞中的 CBY1 蛋白，但不能检测到患者的成纤维细胞中的 CBY1 蛋白。此外，我们观察到患者成纤维细胞纤毛能力降低、纤毛长度增加以及纤毛蛋白 AHI1 和 ARL13B 水平降低。我们的数据显示CBY1 LOF 变异体引起具有 Joubert 综合征特征的纤毛病。