OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome
OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome
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DOI：
10.1093/hmg/ddv488
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Thauvin-Robinet, Christel
中科院分区：
文献类型：
--
作者：
Chevrier, Veronique;Bruel, Ange-Line;Thauvin-Robinet, Christel
口-面-指（OFD）综合征是一种罕见的异质性疾病，其特征是面部、口腔和四肢的异常相关，一些是由于初级纤毛过渡区或密切相关的中心粒远端蛋白质的突变。这两种结构对于功能性纤毛的形成和发育过程中的信号事件至关重要。我们在这里报告了KIAA0753/OFIP的因果复合杂合突变在一个患有OFD VI综合征的患者。我们发现KIAA0753/OFIP蛋白，其序列在纤毛动物中是保守的，在人类细胞中与中心体/中心粒和中心粒周围卫星结合，并与FOR20和OFD1形成复合物。在RPE1细胞中，这种三元复合物的任何组分的表达减少都会导致向中心体和卫星募集的缺陷。OFD KIAA0753/OFIP突变体失去了与FOR20和OFD1相互作用的能力，这可能是该缺陷的分子基础。我们还发现KIAA0753/OFIP具有微管稳定活性。已知OFD1和FOR20调节中心粒远端完整性，证实该结构元件是纤毛病致病性突变的重要靶标。
Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1. The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites. The OFD KIAA0753/OFIP mutant loses its capacity to interact with FOR20 and OFD1, which may be the molecular basis of the defect. We also show that KIAA0753/OFIP has microtubule-stabilizing activity. OFD1 and FOR20 are known to regulate the integrity of the centriole distal end, confirming that this structural element is a target of importance for pathogenic mutations in ciliopathies.