Roles of the cilium-associated gene CCDC11 in left-right patterning and in laterality disorders in humans
Roles of the cilium-associated gene CCDC11 in left-right patterning and in laterality disorders in humans
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DOI：
10.1387/ijdb.160442yc
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发表时间：
2017-01-01
影响因子：
0.7
通讯作者：
Cinnamon, Yuval
中科院分区：
文献类型：
--
作者：
Gur, Michal;Cohen, Enbal Ben-Tal;Cinnamon, Yuval
轴向决定发生在胚胎发生的早期阶段。侧位模式的缺陷导致内脏器官定位异常，表现为异位综合征，或完全左右倒置，如全位倒置。这些畸形通常与纤毛病有关，如原发性纤毛运动障碍。我们最近在一个阿拉伯-穆斯林血统的近亲家庭中描述了与侧侧性疾病相关的线圈-线圈结构域11 （CCDC11）基因的新突变，该家族的两个受影响的兄弟姐妹表现出不同的表型，一个患有异位综合征，另一个患有非原发性睫状体运动障碍。这项研究进一步表征了CCDC11的作用，以及在患者来源的细胞和作为模式生物的青蛙胚胎中所鉴定的突变对左右轴向模式的影响。我们分析了患者来源的细胞，并操纵了非洲爪蟾蛙胚胎中的Ccdc11水平。患者细胞的纤毛长度比对照组长，CCDC11定位于中心粒和肌动蛋白细胞骨架。突变的截短蛋白积累，也定位于中心粒和肌动蛋白细胞骨架。在青蛙胚胎中，Ccdc11被调控在FoxJ1的下游，全长或截断蛋白的过表达，或基因的下调导致胚胎左右轴向模式的严重破坏。综上所述，我们对患者中CCDC11有害突变的初步描述，目前的结果和最近更多的支持性研究强调了CCDC11在轴向型中的重要作用。
Axial determination occurs during early stages of embryogenesis. Flaws in laterality patterning result in abnormal positioning of visceral organs, as manifested in heterotaxy syndrome, or complete left-right inversion as in situs inversus totalis. These malformations are often associated with ciliopathies, as seen in primary ciliary dyskinesia. We have recently described a novel mutation in the Coiled-Coil Domain-Containing 11 (CCDC11) gene associated with laterality disorders in a consanguineous family of Arab-Muslim origin with two affected siblings presenting with diverse phenotypes, one with heterotaxy syndrome and the other with non-primary ciliary dyskinesia situs inversus totalis. This study further characterizes the roles of CCDC11 and the implications of the identified mutation on left-right axial patterning in patient-derived cells and in the frog embryo as a model organism. We analyzed patient-derived cells and manipulated Ccdc11 levels in Xenopus laevis frog embryos. Cilia length in patient cells was longer than in controls, and CCDC11 was localized to the centriole and the actin cytoskeleton. Mutated truncated protein accumulated and was also localized to the centriole and actin cytoskeleton. In frog embryos, Ccdc11 was regulated downstream of FoxJ1, and overexpression of the full-length or truncated protein, or downregulation of the gene resulted in severe disruption of embryonic left-right axial patterning. Taken together, our initial description of the deleterious mutation in CCDC11 in patients, the current results and more recent supportive studies highlight the important role of CCDC11 in axial patterning.