Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia
Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia
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DOI：
10.1136/jmedgenet-2012-100867
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发表时间：
2012-06-01
影响因子：
4
通讯作者：
Amselem, Serge
中科院分区：
文献类型：
--
作者：
Blanchon, Sylvain;Legendre, Marie;Amselem, Serge
背景CCDC 39和CCDC 40基因最近被认为与原发性纤毛运动障碍（PCD）伴内部动力蛋白臂（IDA）缺陷和轴丝紊乱有关;然而，它们对疾病的作用尚不清楚。目的描绘CCDC 39/CCDC 40突变谱和相关的表型，本研究筛选了一个大的队列患者IDA的缺陷，在其中的临床和睫状体phenotypes.Methods所有CCDC 39和CCDC 40外显子和内含子边界测序43例来自40个无关的家庭。该研究记录并比较了临床特征（性别、出身、血缘、偏侧性缺陷、首次出现症状和表型评估时的年龄、新生儿呼吸窘迫、气道感染、鼻息肉病、中耳炎、支气管扩张、不孕症）、纤毛搏动频率，结果30/34例患者存在双等位基因CCDC 39或CCDC 40突变（88.2%）与IDA缺陷相关的轴丝解体（分别为22和8个家庭）无关的家庭。在28个已鉴定的突变中，有14个是新的。在6个孤立性IDA缺陷家系中未发现突变。在临床特征和睫状体结构和功能方面，具有确定的突变的患者具有相似的表型。精子鞭毛的超微结构，分析在4/7不育男性，表现出异常的证据相似的ciliary ones.Conclusions CCDC 39和CCDC 40突变的PCD与IDA缺陷和轴丝解体的主要原因。携带CCDC 39或CCDC 40突变的患者在表型上无法区分。在选定的患者中进行CCDC 39和CCDC 40分析，确保发现突变的概率很高，即使临床或纤毛表型不能优先考虑一种分析。
Background CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described.Methods All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella.Results Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones.Conclusions CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.