Compound Heterozygous Variants in the Coiled-Coil Domain Containing 40 Gene in a Chinese Family with Primary Ciliary Dyskinesia Cause Extreme Phenotypic Diversity in Cilia Ultrastructure.
Compound Heterozygous Variants in the Coiled-Coil Domain Containing 40 Gene in a Chinese Family with Primary Ciliary Dyskinesia Cause Extreme Phenotypic Diversity in Cilia Ultrastructure.
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DOI：
10.3389/fgene.2018.00023
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发表时间：
2018
影响因子：
3.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Yang L;Banerjee S;Cao J;Bai X;Peng Z;Chen H;Huang H;Han P;Feng S;Yi N;Song X;Wu J
目的：原发性睫状肌运动障碍(PCD)是一种罕见的遗传性疾病，表现为反复呼吸道感染和不孕症。超过20个基因的突变与PCD有关，其中包括包含40个螺旋结构域(CCDC40)基因。对一名临床诊断为PCD的中国先证者进行了这些基因的突变分析，以确定该家族疾病的遗传基础。先证者表现为呼吸道粘液纤毛间隙改变，不同程度的粘膜充血和水肿，左/右体不对称，不育，精子和细支气管区纤毛超微结构异常。方法：对先证者的DNA进行靶向下一代测序，分析已知的PCD基因亚群的遗传变异，以了解本家族PCD的分子和遗传学基础。通过Sanger测序和Q-PCR验证了靶向下一代测序的结果。结果：靶向下一代测序发现CCDC40基因有两个新的突变(c.1259delA和ex1720缺失)，导致CCDC40mRNA表达异常。这两个新的变异体导致轴丝组织紊乱，导致先证者精子活力降低和纤毛超微结构的表型多样性。结论：这些发现突出了CCDC40突变作为PCD患者新的候选基因检测的重要性，以及ICSI治疗对受这种睫状肌运动障碍影响的家庭的关键作用。我们的研究结果表明，我们的工作丰富了纤毛超微结构的表现，这是以前在PCD患者中没有报道的。
Purpose: Primary ciliary dyskinesia (PCD) is a rare genetic disorder manifested with recurrent infections of respiratory tract and infertility. Mutations in more than 20 genes including the Coiled-Coil Domain Containing 40 (CCDC40) gene are associated with PCD. A Chinese proband with a clinical diagnosis of PCD was analyzed for mutations in these genes to identify the genetic basis of the disease in the family. The proband showed altered mucociliary clearance of the airways, various degree of hyperemia and edema of the mucous membrane, left/right body asymmetry, infertility and ultrastructural abnormality of cilia in both sperm and bronchioles. Methods: The DNA from the proband was analyzed for genetic variation in a subset of genes known to cause PCD using targeted next generation sequencing in order to understand the molecular and genetic basis of the PCD in present family. The result of targeted next generation sequencing has been validated by Sanger sequencing and q-PCR. Results: Targeted next-generation sequencing identified two novel mutations (c.1259delA and EX17_20 deletion) in CCDC40 gene that causes abnormal CCDC40 mRNA expression. These two novel variants cause disorganization of axoneme filaments, which resulted in reduction of sperm motility and phenotypic diversity in ultrastructure of cilia in the proband. Conclusion: These findings highlight the significance of the mutations in CCDC40 as novel candidates for genetic testing in PCD patients as well as the key role of ICSI treatment for the families affected by this ciliary dysmotility. Our findings showed that our work enriched the performance of cilia ultrastructure which were not previously reported in PCD patients.