Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia
Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia
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DOI：
10.1086/302683
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发表时间：
1999-12-01
影响因子：
9.8
通讯作者：
Duriez, B
中科院分区：
文献类型：
--
作者：
Pennarun, G;Escudier, E;Duriez, B
原发性纤毛运动障碍（PCD）是一组病因不明的异质性疾病，通常以常染色体隐性遗传。其表型的特征是呼吸纤毛和精子尾部的轴丝异常，导致支气管扩张和鼻窦炎，有时与逆位（Kartagener综合征）和男性不育症有关。PCD中的主要纤毛缺陷是动力蛋白臂的缺失。我们已经分离出第一个参与PCD的基因，使用的候选基因的方法开发的基础上记录的异常的不动株的莱茵衣藻，携带轴丝超微结构缺陷，让人想起PCD。利用编码轴丝蛋白基因的进化保守性，我们分离了一个与C. Reinhardtii基因编码动力蛋白中间链，其中突变与外部动力蛋白臂的缺失相关。DNAI 1在气管和睾丸中高表达，由位于9 p13-p21的20个外显子组成。在一名PCD患者中发现了两种DNAI 1功能缺失突变，其特征为呼吸纤毛不动，缺乏动力蛋白外臂。此外，我们排除了该基因与其他五个受影响的家庭中类似的PCD表型之间的联系，提供了一个明确的证明位点异质性。这些数据揭示了DNAI 1在人类轴丝结构发育中的关键作用，并为鉴定参与相关发育缺陷的其他基因开辟了新途径。
Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of unknown origin, usually inherited as an autosomal recessive trait. Its phenotype is characterized by axonemal abnormalities of respiratory cilia and sperm tails leading to bronchiectasis and sinusitis, which are sometimes associated with situs inversus (Kartagener syndrome) and male sterility. The main ciliary defect in PCD is an absence of dynein arms. We have isolated the first gene involved in PCD, using a candidate-gene approach developed on the basis of documented abnormalities of immotile strains of Chlamydomonas reinhardtii, which carry axonemal ultrastructural defects reminiscent of PCD. Taking advantage of the evolutionary conservation of genes encoding axonemal proteins, we have isolated a human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein intermediate chain in which mutations are associated with the absence of outer dynein arms. DNAI1 is highly expressed in trachea and testis and is composed of 20 exons located at 9p13-p21. Two loss-of-function mutations of DNAI1 have been identified in a patient with PCD characterized by immotile respiratory cilia lacking outer dynein arms. In addition, we excluded linkage between this gene and similar PCD phenotypes in five other affected families, providing a clear demonstration of locus heterogeneity. These data reveal the critical role of DNAI1 in the development of human axonemal structures and open up new means for identification of additional genes involved in related developmental defects.