The emerging genetics of primary ciliary dyskinesia.
The emerging genetics of primary ciliary dyskinesia.
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DOI：
10.1513/pats.201103-023sd
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Ferkol, Thomas W
中科院分区：
文献类型：
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作者：
Zariwala, Maimoona A;Omran, Heymut;Ferkol, Thomas W
原发性纤毛运动障碍（primaryciliarydyskinesia，PCD）是一种罕见的常染色体隐性遗传疾病，其特征是由于纤毛结构和功能异常而导致的耳-鼻-肺疾病和位置异常（Kartagener综合征）。大多数患者目前被诊断为PCD的基础上存在的缺陷睫状体超微结构。然而，由于临床表型和睫状体超微结构的变化，诊断往往仍然具有挑战性。部分PCD患者纤毛超微结构正常，这进一步混淆了诊断。PCD的基因测试存在，但价值有限，因为它只调查了两个基因中有限数量的突变。PCD的遗传学是复杂的，由于轴丝结构的复杂性，这是高度保守的通过进化，这是由多种蛋白质。由于基因座和等位基因的异质性，确定PCD致病基因具有挑战性。尽管存在遗传异质性，但已使用多种工具，目前已知有11种导致PCD的基因。所有这些基因结合起来解释了大约50%的PCD病例;因此，需要鉴定更多的基因。这篇综述简要介绍了目前的知识，关于PCD的遗传学，并侧重于用于确定新的PCD引起的基因，包括候选基因的方法，使用模式生物，下一代大规模并行测序技术，和使用遗传隔离的人群的方法。总之，我们展示了多管齐下的方法，这是必要的，以规避由于遗传异质性的挑战，揭示遗传原因的PCD。
Primary ciliary dyskinesia (PCD) is an autosomal recessive, rare, genetically heterogeneous condition characterized by oto-sino-pulmonary disease together with situs abnormalities (Kartagener syndrome) owing to abnormal ciliary structure and function. Most patients are currently diagnosed with PCD based on the presence of defective ciliary ultrastructure. However, diagnosis often remains challenging due to variability in the clinical phenotype and ciliary ultrastructural changes. Some patients with PCD have normal ciliary ultrastructure, which further confounds the diagnosis. A genetic test for PCD exists but is of limited value because it investigates only a limited number of mutations in only two genes. The genetics of PCD is complicated owing to the complexity of axonemal structure that is highly conserved through evolution, which is comprised of multiple proteins. Identifying a PCD-causing gene is challenging due to locus and allelic heterogeneity. Despite genetic heterogeneity, multiple tools have been used, and there are 11 known PCD-causing genes. All of these genes combined explain approximately 50% of PCD cases; hence, more genes need to be identified. This review briefly describes the current knowledge regarding the genetics of PCD and focuses on the methodologies used to identify novel PCD-causing genes, including a candidate gene approach using model organisms, next-generation massively parallel sequencing techniques, and the use of genetically isolated populations. In conclusion, we demonstrate the multipronged approach that is necessary to circumvent challenges due to genetic heterogeneity to uncover genetic causes of PCD.